Therapeutic compounds and uses thereof

ABSTRACT

The present invention relates to a compound formula (I): 
                         
and to salts thereof, wherein R 1 , R 2  X, and Y have any of the values defined herein, and compositions and uses thereof. The compounds are useful as inhibitors of CBP and/or EP300. Also included are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various CBP and/or EP300-mediated disorders.

PRIORITY OF INVENTION

This application is a continuation of International Application No.PCT/US2017/034326, filed 24 May 2017, which claims priority toInternational Patent Application PCT/CN2016/083118, filed 24 May 2016.The entire content of the applications referenced above are herebyincorporated by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been filedelectronically in ASCII format and is hereby incorporated by referencein its entirety. Said ASCII copy, created on Feb. 27, 2019, is named01076_032US1_SL.txt and is 7,162 bytes in size.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors ofCBP/EP300 and methods of treating cancer using such inhibitors.

BACKGROUND OF THE INVENTION

Chromatin is a complex combination of DNA and protein that makes upchromosomes. It is found inside the nuclei of eukaryotic cells and isdivided between heterochromatin (condensed) and euchromatin (extended)forms. The major components of chromatin are DNA and proteins. Histonesare the chief protein components of chromatin, acting as spools aroundwhich DNA winds. The functions of chromatin are to package DNA into asmaller volume to fit in the cell, to strengthen the DNA to allowmitosis and meiosis, and to serve as a mechanism to control expressionand DNA replication. The chromatin structure is controlled by a seriesof post-translational modifications to histone proteins, notablyhistones H3 and H4, and most commonly within the “histone tails” whichextend beyond the core nucleosome structure. Histone tails tend to befree for protein-protein interaction and are also the portion of thehistone most prone to post-translational modification. Thesemodifications include acetylation, methylation, phosphorylation,ubiquitinylation, and SUMOylation. These epigenetic marks are writtenand erased by specific enzymes that place the tags on specific residueswithin the histone tail, thereby forming an epigenetic code, which isthen interpreted by the cell to allow gene specific regulation ofchromatin structure and thereby transcription.

Of all classes of proteins, histones are amongst the most susceptible topost-translational modification. Histone modifications are dynamic, asthey can be added or removed in response to specific stimuli, and thesemodifications direct both structural changes to chromatin andalterations in gene transcription. Distinct classes of enzymes, namelyhistone acetyltransferases (HATs) and histone deacetylases (HDACs),acetylate or de-acetylate specific histone lysine residues (Struhl K.,Genes Dev., 1989, 12, 5, 599-606).

Bromodomains, which are approximately 110 amino acids long, are found ina large number of chromatin-associated proteins and have been identifiedin approximately 70 human proteins, often adjacent to other proteinmotifs (Jeanmougin F., et al., Trends Biochem. Sci., 1997, 22, 5,151-153; and Tamkun J. W., et al., Cell, 1992, 7, 3, 561-572).Interactions between bromodomains and modified histones may be animportant mechanism underlying chromatin structural changes and generegulation. Bromodomain-containing proteins have been implicated indisease processes including cancer, inflammation and viral replication.See, e.g., Prinjha et al., Trends Pharm. Sci., 33(3):146-153 (2012) andMuller et al., Expert Rev., 13(29): 1-20 (September 2011).

Cell-type specificity and proper tissue functionality requires the tightcontrol of distinct transcriptional programs that are intimatelyinfluenced by their environment. Alterations to this transcriptionalhomeostasis are directly associated with numerous disease states, mostnotably cancer, immuno-inflammation, neurological disorders, andmetabolic diseases. Bromodomains reside within key chromatin modifyingcomplexes that serve to control distinctive disease-associatedtranscriptional pathways. This is highlighted by the observation thatmutations in bromodomain-containing proteins are linked to cancer, aswell as immune and neurologic dysfunction. Hence, the selectiveinhibition of bromodomains across a specific family, such as theselective inhibition of a bromodomain of CBP/EP300, creates variedopportunities as novel therapeutic agents in human dysfunction.

There is a need for treatments for cancer, immunological disorders, andother CBP/EP300 bromodomain related diseases.

SUMMARY OF THE INVENTION

Compounds of Formula (I)

One aspect is a compound of formula (I):

or a salt thereof, wherein:

R¹ is C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, 3-12 membered carbocycle,and 3-12 membered heterocycle, wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl,C₂₋₁₂alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle ofR¹ is optionally substituted with one or more groups R^(d);

R² is —C(O)—N(R^(e))₂, —S(O)—N(R^(e))₂, —S(O)₂—N(R^(e))₂, —C(O)—R^(e),—C(O)—O—R^(e), —S(O)—R^(e), or —S(O)₂—R^(e),

X is absent, —C(═O)—, or C₁₋₃alkyl; and Y is phenyl, a 9-memberedbicyclic carbocycle, a 10-membered bicyclic carbocycle, a 9-memberedbicyclic heterocycle, or a 10-membered bicyclic heterocycle, wherein Yis optionally substituted with R^(a) and wherein Y is further optionallysubstituted with one or more groups R^(b);

or wherein —X—Y taken together is selected from the group consisting of:

each R^(a) is independently selected from the group consisting of a5-membered carbocycle, a 6-membered carbocycle, a 5-memberedheterocycle, and a 6-membered heterocycle, which a 5-memberedcarbocycle, 6-membered carbocycle, 5-membered heterocycle, and6-membered heterocycle are optionally substituted with one or moregroups R^(c);

each R^(b) is independently selected from the group consisting of a5-membered amino, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₂₋₆cycloalkyl,(C₂₋₆cycloalkyl) C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₄alkanoyl, —C(O)—N(R^(f))₂, —N(R^(f))C(O)—R^(f), and C₁₋₄alkanoyloxy,wherein each C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₂₋₆cycloalkyl,(C₂₋₆cycloalkyl) C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₄alkanoyl, and C₁₋₄alkanoyloxy, is optionally substituted with one ormore groups independently selected from oxo, halo, amino, hydroxy,C₁₋₃alkoxy, and C₁-C₃ alkyl that is optionally substituted with one ormore groups independently selected from halo;

each R^(c) is independently selected from the group consisting of halo,cyano, hydroxy, amino, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₂₋₆cycloalkyl, (C₂₋₆cycloalkyl) C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, and C₁₋₄alkanoyloxy, wherein eachC₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₂₋₆cycloalkyl, (C₂₋₆cycloalkyl)C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, andC₁₋₄alkanoyloxy, is optionally substituted with one or more groupsindependently selected from oxo, halo, amino, hydroxy, C₁₋₃alkoxy, andC₁-C₃ alkyl that is optionally substituted with one or more groupsindependently selected from halo;

each R^(d) is independently selected from the group consisting of oxo,halo, cyano, hydroxy, amino, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₂₋₆cycloalkyl, (C₂₋₆cycloalkyl) C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, and C₁₋₄alkanoyloxy, wherein eachC₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₂₋₆cycloalkyl, (C₂₋₆cycloalkyl)C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, andC₁₋₄alkanoyloxy, is optionally substituted with one or more groupsindependently selected from oxo, halo, amino, hydroxy, C₁₋₃alkoxy, andC₁-C₃ alkyl that is optionally substituted with one or more groupsindependently selected from halo;

each R^(e) is independently selected from hydrogen, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, and C₂₋₅cycloalkyl, wherein each C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, and C₂₋₅cycloalkyl is optionally substitutedwith one or more groups independently selected from oxo, halo, amino,hydroxyl, C₁₋₃alkoxy, and C₁-C₃ alkyl that is optionally substitutedwith one or more groups independently selected from halo; and

each R^(f) is independently selected from hydrogen and C₁₋₄alkyl;

or a compound selected from the group consisting of:

or a salt thereof.

Another aspect is a compound of formula (I):

or a salt thereof, wherein:

R¹ is C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, 3-12 membered carbocycle,and 3-12 membered heterocycle, wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl,C₂₋₁₂alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle ofR¹ is optionally substituted with one or more groups R^(d);

R² is —C(O)—N(R^(e))₂, —S(O)—N(R^(e))₂, —S(O)₂—N(R^(e))₂, —C(O)—R^(e),—C(O)—O—R^(e), —S(O)—R^(e), or —S(O)₂—R^(e),

X is absent, —C(═O)—, or C₁₋₃alkyl;

Y is phenyl, a 9-membered bicyclic carbocycle, a 10-membered bicycliccarbocycle, a 9-membered bicyclic heterocycle, or a 10-membered bicyclicheterocycle, wherein Y is optionally substituted with R^(a) and whereinY is further optionally substituted with one or more groups R^(b);

each R^(a) is independently selected from the group consisting of a5-membered carbocycle, a 6-membered carbocycle, a 5-memberedheterocycle, and a 6-membered heterocycle, which a 5-memberedcarbocycle, 6-membered carbocycle, 5-membered heterocycle, and6-membered heterocycle are optionally substituted with one or moregroups R^(c);

each R^(b) is independently selected from the group consisting of halo,cyano, hydroxy, amino, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₂₋₆cycloalkyl, (C₂₋₆cycloalkyl) C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, —C(O)—N(R^(f))₂, —N(R^(f))C(O)—R^(f),and C₁₋₄alkanoyloxy, wherein each C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₂₋₆cycloalkyl, (C₂₋₆cycloalkyl) C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, and C₁₋₄alkanoyloxy, is optionallysubstituted with one or more groups independently selected from oxo,halo, amino, hydroxy, C₁₋₃alkoxy, and C₁-C₃ alkyl that is optionallysubstituted with one or more groups independently selected from halo;

each R^(c) is independently selected from the group consisting of halo,cyano, hydroxy, amino, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₂₋₆cycloalkyl, (C₂₋₆cycloalkyl) C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, and C₁₋₄alkanoyloxy, wherein eachC₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₂₋₆cycloalkyl, (C₂₋₆cycloalkyl)C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, andC₁₋₄alkanoyloxy, is optionally substituted with one or more groupsindependently selected from oxo, halo, amino, hydroxy, C₁₋₃alkoxy, andC₁-C₃ alkyl that is optionally substituted with one or more groupsindependently selected from halo;

each R^(d) is independently selected from the group consisting of oxo,halo, cyano, hydroxy, amino, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₂₋₆cycloalkyl, (C₂₋₆cycloalkyl) C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, and C₁₋₄alkanoyloxy, wherein eachC₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₂₋₆cycloalkyl, (C₂₋₆cycloalkyl)C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, andC₁₋₄alkanoyloxy, is optionally substituted with one or more groupsindependently selected from oxo, halo, amino, hydroxy, C₁₋₃alkoxy, andC₁-C₃ alkyl that is optionally substituted with one or more groupsindependently selected from halo;

each R^(e) is independently selected from hydrogen, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, and C₂₋₅cycloalkyl, wherein each C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, and C₂₋₅cycloalkyl is optionally substitutedwith one or more groups independently selected from oxo, halo, amino,hydroxyl, C₁₋₃alkoxy, and C₁-C₃ alkyl that is optionally substitutedwith one or more groups independently selected from halo; and

each R^(f) is independently selected from hydrogen and C₁₋₄alkyl.

Another aspect includes a composition comprising a compound of formula(I) or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable adjuvant, carrier, or vehicle.

Another aspect includes a method for treating a CBP and/orEP300-mediated disorder in an animal comprising administering a compoundof formula (I) or a pharmaceutically acceptable salt thereof to theanimal.

Another aspect includes a method for treating a CBP and/orEP300-mediated disorder in an animal, wherein the disorder is cancer,comprising administering a compound of formula (I) or a pharmaceuticallyacceptable salt thereof to the animal.

Another aspect includes a method for treating a CBP and/orEP300-mediated disorder in an animal, wherein the disorder is a fibroticdisease, comprising administering a compound of formula (I) or apharmaceutically acceptable salt thereof to the animal.

Another aspect includes a method for treating a CBP and/orEP300-mediated disorder in an animal, wherein the disorder is a fibroticlung disease, comprising administering a compound of formula (I) or apharmaceutically acceptable salt thereof to the animal.

Another aspect includes a compound of formula (I) or a pharmaceuticallyacceptable salt thereof for use in medical therapy.

Another aspect includes a compound of formula (I) or a pharmaceuticallyacceptable salt thereof for the prophylactic or therapeutic treatment ofa CBP and/or EP300-mediated disorder.

Another aspect includes the use of a compound of formula (I) or apharmaceutically acceptable salt thereof to prepare a medicament fortreating a CBP and/or EP300-mediated disorder in an animal (e.g. amammal such as a human).

Another aspect includes compounds for the study of CBP and/or EP300.

Another aspect includes synthetic intermediates and synthetic processesdisclosed herein that are useful for preparing a compound of formula (I)or a salt thereof.

DETAILED DESCRIPTION Compounds and Definitions

Definitions and terms are described in more detail below. Chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.

Unless otherwise stated, compounds of formula (I) include enantiomeric,diastereomeric and geometric (or conformational) isomeric forms of agiven structure. For example, the R and S configurations for eachasymmetric center, Z and E double bond isomers, Z and E conformationalisomers, single stereochemical isomers, as well as enantiomeric,diastereomeric, and geometric (or conformational) mixtures are included.Unless otherwise stated, all tautomeric forms of structures depictedherein are included. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds of formula (I), wherein the independent replacement orenrichment of one or more hydrogen by deuterium or tritium, carbon by¹³C- or ¹⁴C carbon, nitrogen by a ¹⁵N nitrogen, sulfur by a ³³S, ³⁴S or³⁶S sulfur, oxygen by a ¹⁷O or ¹⁸O oxygen, or fluorine by a ¹⁸F areincluded. Such compounds are useful, for example, as analytical tools,as probes in biological assays, or as therapeutic agents.

Where a particular enantiomer is described, it may, in certainembodiments be provided substantially free of the correspondingenantiomer, and may also be referred to as “optically enriched.”“Optically-enriched,” as used herein, means that the mixture ofenantiomers is made up of a significantly greater proportion of oneenantiomer, and may be described by enantiomeric excess (ee %). Incertain embodiments, the mixture of enantiomers is made up of at leastabout 90% by weight of a given enantiomer (about 90% ee). In otherembodiments, the mixture of enantiomers is made up of at least about95%, 98% or 99% by weight of a given enantiomer (about 95%, 98% or 99%ee). Enantiomers and diastereomers may be isolated from racemic mixturesby any method known to those skilled in the art, includingrecrystallization from solvents in which one stereoisomer is moresoluble than the other, chiral high pressure liquid chromatography(HPLC), supercritical fluid chromatography (SFC), the formation andcrystallization of chiral salts, which are then separated by any of theabove methods, or prepared by asymmetric syntheses and optionallyfurther enriched. See, for example, Jacques et al., Enantiomers,Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen,et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry ofCarbon Compounds (McGraw-Hill, N Y, 1962); Wilen, S. H. Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972).

The term “heteroatom” means any atom independently selected from an atomother than carbon or hydrogen, for example, one or more of oxygen,sulfur, nitrogen, phosphorus or silicon (including any oxidized form ofnitrogen, sulfur, phosphorus or silicon; and the quaternized form of anynitrogen).

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br)and iodine (iodo, —I).

The term “oxo” refers to ═O.

The term “amino” includes —NH₂, —NH(C₁-C₃alkyl), and —N(C₁-C₃alkyl)₂.

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “carbocyclyl” used alone or as part of a larger moiety, refersto a saturated, partially unsaturated, or aromatic ring system having 3to 20 carbon atoms. In one embodiment, carbocyclyl includes 3 to 12carbon atoms (C₃-C₁₂). In another embodiment, carbocyclyl includesC₃-C₈, C₃-C₁₀ or C₅-C₁₀. In other embodiment, carbocyclyl, as amonocycle, includes C₃-C₈, C₃-C₆ or C₅-C₆. In another embodiment,carbocyclyl, as a bicycle, includes C₇-C₁₂. In another embodiment,carbocyclyl, as a spiro system, includes C₅-C₁₂. Examples of monocycliccarbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicycliccarbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5],[5,5], [5,6] or [6,6] ring systems, for example bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane; and spirocarbocyclyls include spiro[2.2]pentane, spiro[2.3]hexane,spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane. The termcarbocyclyl includes aryl ring systems as defined herein. The termcarbocycyl also includes cycloalkyl rings (e.g. saturated or partiallyunsaturated mono-, bi-, or spiro-carbocycles).

The term “alkyl,” as used herein, refers to a saturated linear orbranched-chain hydrocarbon radical. In one embodiment, the alkyl radicalis one to eighteen carbon atoms (C₁-C₁₈). In other embodiments, thealkyl radical is C₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆,C₁-C₅, C₁-C₄ or C₁-C₃. C₀ alkyl refers to a bond. Examples of alkylgroups include methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr,n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl(n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, heptyl, octyl, nonyl, decyl,undecyl and dodecyl.

The term “alkenyl,” as used herein, denotes a linear or branched-chainhydrocarbon radical with at least one carbon-carbon double bond. Analkenyl includes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations. In one example, the alkenylradical is two to eighteen carbon atoms (C₂-C₁₈). In other examples, thealkenyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃. Examplesinclude, but are not limited to, ethenyl or vinyl (—CH═CH₂), prop-1-enyl(—CH═CHCH₃), prop-2-enyl (—CH₂CH═CH₂), 2-methylprop-1-enyl, but-1-enyl,but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene,hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.

The term “alkynyl,” as used herein, refers to a linear or branchedhydrocarbon radical with at least one carbon-carbon triple bond. In oneexample, the alkynyl radical is two to eighteen carbon atoms (C₂-C₁₈).In other examples, the alkynyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆or C₂-C₃. Examples include, but are not limited to, ethynyl (—C≡CH),prop-1-ynyl (—C≡CCH₃), prop-2-ynyl (propargyl, —CH₂C≡CH), but-1-ynyl,but-2-ynyl and but-3-ynyl.

The term “alkoxy” refers to a linear or branched radical represented bythe formula —OR in which R is alkyl, alkenyl, alkynyl or carbocycyl.Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, andcyclopropoxy.

The term “haloalkyl,” as used herein, refers to an alkyl as definedherein that is substituted with one or more (e.g. 1, 2, 3, or 4) halogroups.

The term “aryl” used alone or as part of a larger moiety as in“arylalkyl”, “arylalkoxy”, or “aryloxyalkyl”, refers to a monocyclic,bicyclic or tricyclic, carbon ring system, that includes fused rings,wherein at least one ring in the system is aromatic. The term “aryl” maybe used interchangeably with the term “aryl ring”. In one embodiment,aryl includes groups having 6-20 carbon atoms (C₆-C₂₀ aryl). In anotherembodiment, aryl includes groups having 6-10 carbon atoms (C₆-C₁₀ aryl).Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl,phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl,2,3-dihydro-1H-indenyl, and the like, which may be substituted orindependently substituted by one or more substituents described herein.A particular aryl is phenyl. In another embodiment aryl includes an arylring fused to one or more carbocyclic rings, such as indanyl,dihydrophenanthryl, or tetrahydronaphthyl, and the like, where theradical or point of attachment is on an aromatic ring.

The term “heteroaryl” used alone or as part of a larger moiety, e.g.,“heteroarylalkyl”, or “heteroarylalkoxy”, refers to a monocyclic,bicyclic or tricyclic ring system having 5 to 14 ring atoms, wherein atleast one ring is aromatic and contains at least one heteroatom. In oneembodiment, heteroaryl includes 4-6 membered monocyclic aromatic groupswhere one or more ring atoms is nitrogen, sulfur or oxygen that isindependently optionally substituted. In another embodiment, heteroarylincludes 5-6 membered monocyclic aromatic groups where one or more ringatoms is nitrogen, sulfur or oxygen that is independently optionallysubstituted. In some embodiments, the heteroaryl group is a C₁-C₂₀heteroaryl group, where the heteroaryl ring contains 1-20 carbon atomsand the remaining ring atoms include one or more nitrogen, sulfur, oroxygen atoms. Example heteroaryl groups include thienyl, furyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl,oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl,tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl,purinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl,benzotriazolyl, benzoimidazolyl, indolyl, 1,3-thiazol-2-yl,1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl,1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl,1,2,3-triazol-5-yl, pyrid-2-yl N-oxide, and pyrazolo[4,3-c]pyridinyl.The terms “heteroaryl” also includes groups in which a heteroaryl isfused to one or more aryl, carbocyclyl, or heterocyclyl rings, where theradical or point of attachment is on the heteroaryl ring. Nonlimitingexamples include indolyl, isoindolyl, benzothienyl, benzofuranyl,dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono-, bi-or tri-cyclic.

As used herein, the term “heterocyclyl” or “heterocycle” refers to a“carbocyclyl” as defined herein, wherein one or more (e.g. 1, 2, 3, or4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S).In some embodiments, a heterocyclyl or heterocycle refers to a saturatedring system, such as a 3 to 12 membered saturated heterocyclyl ringsystem. In some embodiments, a heterocyclyl or heterocycle refers to aheteroaryl ring system, such as a 5 to 14 membered heteroaryl ringsystem. A heterocyclyl or heterocycle can optionally be substituted withone or more substituents independently selected from those definedherein.

In one example, heterocyclyl or heterocycle includes 3-12 ring atoms andincludes monocycles, bicycles, tricycles and spiro ring systems, whereinthe ring atoms are carbon, and one to five ring atoms is a heteroatomselected from nitrogen, sulfur or oxygen, which is independentlyoptionally substituted by one or more groups. In one example,heterocyclyl or heterocycle includes 1 to 4 heteroatoms. In anotherexample, heterocyclyl or heterocycle includes 3- to 7-memberedmonocycles having one or more heteroatoms selected from nitrogen, sulfuror oxygen. In another example, heterocyclyl or heterocycle includes 4-to 6-membered monocycles having one or more heteroatoms selected fromnitrogen, sulfur or oxygen. In another example, heterocyclyl orheterocycle includes 3-membered monocycles. In another example,heterocyclyl or heterocycle includes 4-membered monocycles. In anotherexample, heterocyclyl or heterocycle includes 5-6 membered monocycles.In one example, the heterocyclyl or heterocycle group includes 0 to 3double bonds. Any nitrogen or sulfur heteroatom may optionally beoxidized (e.g. NO, SO, SO₂), and any nitrogen heteroatom may optionallybe quaternized (e.g. [NR₄]⁺Cl⁻, [NR₄]⁺OH⁻). Example heterocyclyls orheterocycles include oxiranyl, aziridinyl, thiiranyl, azetidinyl,oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl,dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl,tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl,tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl,oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl,azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl,1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl,tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl,1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl,4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl,4,5,6,7-tetrahydrobenzo[d]imidazolyl,1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl,pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl,piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl,3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl,8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl,8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane,azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl,1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl,octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl,1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyls orheterocycles containing a sulfur or oxygen atom and one to threenitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-ylN-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl and1,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, andoxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl.Example 5-membered ring heterocyclyls or heterocycles containing 2 to 4nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl,such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, andtetrazolyl, such as 1H-tetrazol-5-yl. Example benzo-fused 5-memberedheterocyclyls or heterocycles are benzoxazol-2-yl, benzthiazol-2-yl andbenzimidazol-2-yl. Example 6-membered heterocyclyls or heterocyclescontain one to three nitrogen atoms and optionally a sulfur or oxygenatom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, andpyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl,such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, inparticular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides andpyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl,pyridazinyl and the 1,3,4-triazin-2-yl groups, are other exampleheterocyclyl groups.

The term “heterocyclyl” or “heterocycle” also includes groups in which aheterocyclyl is fused to one or more aryl, carbocyclyl, or heterocyclylrings, where the radical or point of attachment is on the heterocyclylring. Nonlimiting examples include tetrahydroquinolinyl andtetrahydroisoquinolinyl.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms butthe ring moiety is not aromatic.

As used herein, the term “inhibitor” refers to a compound that binds toand inhibits the bromodomain of CBP and/or EP300 with measurableaffinity and activity. In certain embodiments, an inhibitor has an IC₅₀or binding constant of less about 20 μM, less than about 1 μM, less thanabout 500 nM, less than about 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, refer to a measurable reduction in activity (e.g., reduction inrecognition of lysine acetyl recognition of chromatin) of thebromodomain of CBP and/or EP300 between: (i) a sample comprising acompound of formula (I) or composition thereof and such bromodomain, and(ii) an equivalent sample comprising such bromodomain, in the absence ofsaid compound, or composition thereof.

“Pharmaceutically acceptable salts” include both acid and base additionsalts. It is to be understood that when a compound or Example herein isshown as a specific salt, the corresponding free-base, as well as othersalts of the corresponding free-base (including pharmaceuticallyacceptable salts of the corresponding free-base) are contemplated.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases and which are not biologically or otherwise undesirable, formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like,and organic acids may be selected from aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids such as formic acid, acetic acid, propionic acid, glycolicacid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid,citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilicacid, benzoic acid, cinnamic acid, mandelic acid, embonic acid,phenylacetic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, salicyclic acid and thelike.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases includes salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particular organicnon-toxic bases are isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline, and caffeine.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the present invention. Examples of solventsinclude water, isopropanol, ethanol, methanol, DMSO, ethyl acetate,acetic acid and ethanolamine. The term “hydrate” refers to the complexwhere the solvent molecule is water.

“Therapeutically effective amount” refers to an amount of a compound ofthe present invention that (i) treats the particular disease, conditionor disorder, (ii) attenuates, ameliorates or eliminates one or moresymptoms of the particular disease, condition, or disorder, or (iii)delays the onset of one or more symptoms of the particular disease,condition or disorder described herein. In the case of cancer, thetherapeutically effective amount of the drug may reduce the number ofcancer cells; reduce the tumor size; inhibit (i.e., slow to some extentand preferably stop) cancer cell infiltration into peripheral organs;inhibit (i.e., slow to some extent and preferably stop) tumormetastasis; inhibit, to some extent, tumor growth; and/or relieve tosome extent one or more of the symptoms associated with the cancer. Forcancer therapy, efficacy can, for example, be measured by assessing thetime to disease progression (TTP) and/or determining the response rate(RR). In the case of immunological disorders, the therapeutic effectiveamount is an amount sufficient to decrease or alleviate an allergicdisorder, the symptoms of an autoimmune and/or inflammatory disease, orthe symptoms of an acute inflammatory reaction (e.g. asthma).

“Treatment” (and variations such as “treat” or “treating”) refers toclinical intervention in an attempt to alter the natural course of theindividual or cell being treated, and can be performed either forprophylaxis or during the course of clinical pathology. Desirableeffects of treatment include one or more of preventing recurrence ofdisease, alleviation of symptoms, diminishment of any direct or indirectpathological consequences of the disease, stabilized (i.e., notworsening) state of disease, preventing metastasis, decreasing the rateof disease progression, amelioration or palliation of the disease state,prolonging survival as compared to expected survival if not receivingtreatment and remission or improved prognosis. In certain embodiments, acompound of formula (I) is used to delay development of a disease ordisorder or to slow the progression of a disease or disorder. Thoseindividuals in need of treatment include those already with thecondition or disorder as well as those prone to have the condition ordisorder, (for example, through a genetic mutation or abberentexpression of a gene or protein).

“CBP/EP300 bromodomain inhibitor” or “CBP and/or EP300 bromodomaininhibitor” refers to a compound that binds to the CBP bromodomain and/orEP300 bromodomain and inhibits and/or reduces a biological activity ofCBP and/or EP300. In some embodiments, CBP/EP300 bromodomain inhibitorbinds to the CBP and/or EP300 primarily (e.g., solely) through contactsand/or interactions with the CBP bromodomain and/or EP300 bromodomain.In some embodiments, CBP/EP300 bromodomain inhibitor binds to the CBPand/or EP300 through contacts and/or interactions with the CBPbromodomain and/or EP300 bromodomain as well as additional CBP and/orEP300 residues and/or domains. In some embodiments, CBP/EP300bromodomain inhibitor substantially or completely inhibits thebiological activity of the CBP and/or EP300. In some embodiments, thebiological activity is binding of the bromodomain of CBP and/or EP300 tochromatin (e.g., histones associated with DNA) and/or another acetylatedprotein. In certain embodiments, the CBP/EP300 bromodomain inhibitorblocks CBP/EP300 activity so as to restore a functional response byT-cells (e.g., proliferation, cytokine production, target cell killing)from a dysfunctional state to antigen stimulation. In some embodiments,the CBP/EP300 bromodomain inhibitor binds to and inhibits CBPbromodomain. In some embodiments, the CBP/EP300 bromodomain inhibitorbinds to and inhibits EP300 bromodomain.

As used herein, “a” or “an” means one or more, unless clearly indicatedotherwise. As used herein, “another” means at least a second or more.

Exemplary Values for Compounds of Formula (I)

In certain embodiments the compound is a compound of formula (Id):

or a salt thereof, wherein:

U is CH or N; V is CH; and W is CH or N; or

U is CH or N; V is N; and W is CH; and

one of R³, R⁴, and R⁵ is selected from the group consisting of hydrogenand R^(a) and the remainder of R³, R⁴, and R⁵ R^(b) are independentlyselected from the group consisting of hydrogen, halo, cyano, hydroxy,amino, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₂₋₆cycloalkyl,(C₂₋₆cycloalkyl) C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₄alkanoyl, and C₁₋₄alkanoyloxy, wherein each C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, C₂₋₆cycloalkyl, (C₂₋₆cycloalkyl) C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyl, and C₁₋₄alkanoyloxy, is optionallysubstituted with one or more groups independently selected from oxo,halo, amino, hydroxy, C₁₋₃alkoxy, and C₁-C₃ alkyl that is optionallysubstituted with one or more groups independently selected from halo.

In certain embodiments the compound is a compound of formula (Ia):

or a salt thereof.

In certain embodiments the compound is a compound of formula (Ib):

or a salt thereof.

In certain embodiments the compound is a compound of formula (Ic):

or a salt thereof.

In certain embodiments R¹ is C₁₋₁₂alkyl or 3-12 membered heterocycle,wherein each C₁₋₁₂alkyl and 3-12 membered heterocycle of R¹ isoptionally substituted with one or more groups R^(d).

In certain embodiments R¹ is C₁₋₃alkyl or 3-6 membered heterocycle,wherein each C₁₋₃alkyl or 3-6 membered heterocycle of R¹ is optionallysubstituted with one or more groups R^(d).

In certain embodiments R¹ is C₁₋₃alkyl or 3-6 membered heterocycle,wherein each C₁₋₃alkyl or 3-6 membered heterocycle of R¹ is optionallysubstituted with one or more groups independently selected from thegroup consisting of oxo, halo, C₂₋₆cycloalkyl, and C₁₋₄alkoxy.

In certain embodiments R¹ is selected from the group consisting of:methyl,

In certain embodiments R¹ is:

In certain embodiments R² is C₁₋₄alkanoyl

In certain embodiments R² is selected from the group consisting of:

In certain embodiments R² is —C(═O)CH₃.

In certain embodiments Y is phenyl, wherein Y is optionally substitutedwith R^(a) and wherein Y is further optionally substituted with one ormore groups R^(b).

In certain embodiments Y is 9-membered bicyclic carbocycle or a10-membered bicyclic carbocycle, wherein Y is optionally substitutedwith R^(a) and wherein Y is further optionally substituted with one ormore groups R^(b).

In certain embodiments Y is a 9-membered bicyclic heterocycle or a10-membered bicyclic heterocycle, wherein Y is optionally substitutedwith R^(a) and wherein Y is further optionally substituted with one ormore groups R^(b).

In certain embodiments —X—Y is selected from the group consisting of:

In certain embodiments Y is selected from the group consisting of:

In certain embodiments —X—Y is selected from the group consisting of:

In certain embodiments —X—Y is selected from the group consisting of:

In certain embodiments —X—Y is selected from the group consisting of:

In certain embodiments Y is selected from the group consisting of:

In certain embodiments —X—Y is selected from the group consisting of:

In certain embodiments the compound or salt is selected from the groupconsisting of:

and salts thereof.Uses, Formulation and Administration of Compounds of Formula (I)Pharmaceutically Acceptable Compositions

Another aspect includes a pharmaceutical composition comprising acompound of formula (I) or a pharmaceutically acceptable salt thereof.In one embodiment, the composition further comprises a pharmaceuticallyacceptable carrier, adjuvant, or vehicle. In another embodiment, thecomposition further comprises an amount of the compound effective tomeasurably inhibit a bromodomain of CBP and/or EP300. In certainembodiments, the composition is formulated for administration to apatient in need thereof.

The term “patient” or “individual” as used herein, refers to an animal,such as a mammal, such as a human. In one embodiment, patient orindividual refers to a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Compositions comprising a compound of formula (I) or salt thereof may beadministered orally, parenterally, by inhalation spray, topically,transdermally, rectally, nasally, buccally, sublingually, vaginally,intraperitoneal, intrapulmonary, intradermal, epidural or via animplanted reservoir. The term “parenteral” as used herein includessubcutaneous, intravenous, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques.

In one embodiment, the composition comprising a compound of formula (I)or salt thereof is formulated as a solid dosage form for oraladministration. Solid dosage forms for oral administration includecapsules, tablets, pills, powders, and granules. In certain embodiments,the solid oral dosage form comprising a compound of formula (I) or asalt thereof further comprises one or more of (i) an inert,pharmaceutically acceptable excipient or carrier, such as sodium citrateor dicalcium phosphate, and (ii) filler or extender such as starches,lactose, sucrose, glucose, mannitol, or silicic acid, (iii) binders suchas carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose or acacia, (iv) humectants such as glycerol, (v) disintegratingagent such as agar, calcium carbonate, potato or tapioca starch, alginicacid, certain silicates or sodium carbonate, (vi) solution retardingagents such as paraffin, (vii) absorption accelerators such asquaternary ammonium salts, (viii) a wetting agent such as cetyl alcoholor glycerol monostearate, (ix) absorbent such as kaolin or bentoniteclay, and (x) lubricant such as talc, calcium stearate, magnesiumstearate, polyethylene glycols or sodium lauryl sulfate. In certainembodiments, the solid oral dosage form is formulated as capsules,tablets or pills. In certain embodiments, the solid oral dosage formfurther comprises buffering agents. In certain embodiments, suchcompositions for solid oral dosage forms may be formulated as fillers insoft and hard-filled gelatin capsules comprising one or more excipientssuch as lactose or milk sugar, polyethylene glycols and the like.

In certain embodiments, tablets, dragees, capsules, pills and granulesof the compositions comprising a compound of formula (I) or salt thereofoptionally comprise coatings or shells such as enteric coatings. Theymay optionally comprise opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions includepolymeric substances and waxes, which may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

In another embodiment, a composition comprises micro-encapsulatedcompound of formula (I) or salt thereof, and optionally, furthercomprises one or more excipients.

In another embodiment, compositions comprise liquid dosage formulationscomprising a compound of formula (I) or salt thereof for oraladministration, and optionally further comprise one or more ofpharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In certain embodiments, the liquiddosage form optionally, further comprise one or more of an inert diluentsuch as water or other solvent, a solubilizing agent, and an emulsifiersuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols or fatty acid esters ofsorbitan, and mixtures thereof. In certain embodiments, liquid oralcompositions optionally further comprise one or more adjuvant, such as awetting agent, a suspending agent, a sweetening agent, a flavoring agentand a perfuming agent.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of formula (I), it is oftendesirable to slow the absorption of the compound from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

In certain embodiments, the composition for rectal or vaginaladministration are formulated as suppositories which can be prepared bymixing a compound of formula (I) or a salt thereof with suitablenon-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, for example those which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the compound of formula (I).

Example dosage forms for topical or transdermal administration of acompound of formula (I) include ointments, pastes, creams, lotions,gels, powders, solutions, sprays, inhalants or patches. The compound offormula (I) or a salt thereof is admixed under sterile conditions with apharmaceutically acceptable carrier, and optionally preservatives orbuffers. Additional formulation examples include an ophthalmicformulation, ear drops, eye drops, transdermal patches. Transdermaldosage forms can be made by dissolving or dispensing the compound offormula (I) or a salt thereof in medium, for example ethanol ordimethylsulfoxide. Absorption enhancers can also be used to increase theflux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

Nasal aerosol or inhalation formulations of a compound of formula (I) ora salt thereof may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promotors to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

In certain embodiments, pharmaceutical compositions may be administeredwith or without food. In certain embodiments, pharmaceuticallyacceptable compositions are administered without food. In certainembodiments, pharmaceutically acceptable compositions of this inventionare administered with food.

Specific dosage and treatment regimen for any particular patient willdepend upon a variety of factors, including age, body weight, generalhealth, sex, diet, time of administration, rate of excretion, drugcombination, the judgment of the treating physician, and the severity ofthe particular disease being treated. The amount of a provided compoundof formula (I) or salt thereof in the composition will also depend uponthe particular compound in the composition.

In one embodiment, the therapeutically effective amount of the compoundof the invention administered parenterally per dose will be in the rangeof about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patientbody weight per day, with the typical initial range of compound usedbeing 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosageforms, such as tablets and capsules, contain from about 5 to about 100mg of the compound of the invention.

An example tablet oral dosage form comprises about 2 mg, 5 mg, 25 mg, 50mg, 100 mg, 250 mg or 500 mg of a compound of formula (I) or saltthereof, and further comprises about 5-30 mg anhydrous lactose, about5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP)K30 and about 1-10 mg magnesium stearate. The process of formulating thetablet comprises mixing the powdered ingredients together and furthermixing with a solution of the PVP. The resulting composition can bedried, granulated, mixed with the magnesium stearate and compressed totablet form using conventional equipment. An example of an aerosolformulation can be prepared by dissolving about 2-500 mg of a compoundof formula (I) or salt thereof, in a suitable buffer solution, e.g. aphosphate buffer, and adding a tonicifier, e.g. a salt such sodiumchloride, if desired. The solution may be filtered, e.g. using a 0.2micron filter, to remove impurities and contaminants.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Another aspect includes the use of a compound of formula (I) or a saltthereof for the inhibition of a bromodomain (in vitro or in vivo) (e.g.,in vitro or in vivo inhibition of the bromodomain of CBP/EP300).

Another embodiment includes a method for treating a bromodomain-mediateddisorder (e.g., CBP/EP300 bromodomain-mediated disorder) in an animalcomprising administering a compound of formula (I), or apharmaceutically acceptable salt thereof to the animal.CBP/EP300-mediated disorders include, but are not limited to thosedisorders described herein.

Another embodiment includes a method of increasing efficacy of a cancertreatment comprising a cytotoxic agent in an animal comprisingadministering to the animal an effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof.

Another embodiment includes a method of extending the duration ofresponse to a cancer therapy in an animal, comprising administering toan animal undergoing the cancer therapy a compound of formula (I) or apharmaceutically acceptable salt thereof, wherein the duration ofresponse to the cancer therapy when the compound of formula (I) or thepharmaceutically acceptable salt thereof is administered is extendedover the duration of response to the cancer therapy in the absence ofthe administration of the compound of formula (I) or thepharmaceutically acceptable salt thereof.

Another embodiment includes a method of treating cancer in an individualcomprising administering to the individual (a) a compound of formula (I)or a pharmaceutically acceptable salt thereof, and (b) a cytotoxicagent. In one embodiment the cytotoxic agent is selected fromanti-microtubule agents, platinum coordination complexes, alkylatingagents, antibiotic agents, topoisomerase II inhibitors, antimetabolites,topoisomerase I inhibitors, hormones and hormonal analogues, signaltransduction pathway inhibitors, non-receptor tyrosine kinaseangiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents,inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cyclesignaling inhibitors, HDAC inhibitors, proteasome inhibitors, andinhibitors of cancer metabolism. In one embodiment the cytotoxic agentis a taxane. In one embodiment the taxane is paclitaxel or docetaxel. Inone embodiment the cytotoxic agent is a platinum agent. In oneembodiment the cytotoxic agent is an antagonist of EGFR. In oneembodiment the antagonist of EGFR isN-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine or apharmaceutically acceptable salt thereof (e.g., erlotinib). In oneembodiment the cytotoxic agent is a RAF inhibitor. In one embodiment theRAF inhibitor is a BRAF or CRAF inhibitor. In one embodiment the RAFinhibitor is vemurafenib. In one embodiment the cytotoxic agent is aPI3K inhibitor.

In certain embodiments, treatment may be administered after one or moresymptoms have developed. In other embodiments, treatment may beadministered in the absence of symptoms. For example, treatment may beadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment may also be continued aftersymptoms have resolved, for example to prevent or delay theirrecurrence.

In some embodiments, the CBP/EP300 bromodomain inhibitor interferes withthe associating of CBP and/or EP300 with histones, in particularacetylated lysines in histones. In some embodiments, the CBP/EP300bromodomain inhibitor inhibits binding of CBP and/or EP300 to chromatin(e.g., histone associated DNA). In some embodiments, the CBP/EP300bromodomain inhibitor inhibits and/or reduces binding of the CBPbromodomain and/or EP300 bromodomain to chromatin (e.g., histoneassociated DNA). In some embodiments, the CBP/EP300 bromodomaininhibitor does not affect association of other domains of CBP and/orEP300 to chromatin. In some embodiments, CBP/EP300 bromodomain inhibitorbinds to the CBP and/or EP300 primarily (e.g., solely) through contactsand/or interactions with the CBP bromodomain and/or EP300 bromodomain.In some embodiments, CBP/EP300 bromodomain inhibitor binds to the CBPand/or EP300 through contacts and/or interactions with the CBPbromodomain and/or EP300 bromodomain as well as additional CBP and/orEP300 residues and/or domains. Methods of assaying association withchromatin are known in the art and include, but are not limited to,chromatin fractionation, BRET assay (Promega), FRAP assay, ChromatinImmunoprecipitation (ChIP), biophysical binding assay, and/or HistoneAssociation Assay. See, e.g., Das et al., BioTechniques 37:961-969(2004).

In some embodiments, the CBP/EP300 bromodomain inhibitor does not affecteffector function in CD8 cells (i.e., effector function is substantiallythe same in the presence and/or absence of the CBP/EP300 bromodomaininhibitor). In some embodiments, the CBP/EP300 bromodomain inhibitordoes not affect expression levels of perforin, granzyme, and/or EOMES(i.e., expression levels of one or more perforin, granzyme, and/or EOMESare substantially the same in the presence and/or absence of theCBP/EP300 bromodomain inhibitor). In some embodiments, the CBP/EP300bromodomain inhibitor does not affect expression levels of effectorcytokines IFN-γ and/or TNFα (i.e., expression levels of effectorcytokines IFN-γ and/or TNFα are substantially the same in the presenceand/or absence of the CBP/EP300 bromodomain inhibitor). In someembodiments, the CBP/EP300 bromodomain inhibitor enhances naïve T cellresponsiveness to CD3/CD28 stimulation in the presence of Treg cells.

In some embodiments, the CBP/EP300 bromodomain inhibitor does notsubstantially bind to (e.g., does not bind to) the HAT domain of CBPand/or EP300. In some embodiments, the CBP/EP300 bromodomain inhibitordoes not substantially bind to (e.g., does not bind to) the HAT domainof CBP and/or EP300 as identified in Delvecchio et al., Nat. Struct. &Mol. Biol. 20:1040-1046 (2013), which is incorporated by reference inits entirety. In some embodiments, the CBP/EP300 bromodomain inhibitordoes not substantially bind to one or more residues of the amino acidsequence ENKFSAKRLQTTRLGNHLEDRVNKFLRRQNHPEAGEVFVRVVASSDKTVEVKPGMKSRFVDSGEMSESFPYRTKALFAFEEIDGVDVCFFGMHVQEYGSDCPPPNTRRVYISYLDSIHFFRPRcLRTAVYHEILIGYLEYVKKLGYVTGHIWACPPSEGDDYIFHCHPPDQKIPKPKRLQEWYKKMLDKAFAERIIHDYKDIFKQATEDRLTSAKELPYFEGDFWPNVLEESIKELEQEEEERKKEESTAASETTEGSQGDSKNAKKKNNKKTNKNKSSISRANKKKPSMPNVSNDLSQKLYATMEKHKEVFFVIHLHAGPVINTLPPIVDPDPLLSCDLMDGRDAFLTLARDKHWEFSSLRRSKWSTLCMLVELHTQGQD (amino acid residues 1321-1701 of UniProt No. Q92793 (SEQID NO: 1)). In some embodiments, the CBP/EP300 bromodomain inhibitordoes not substantially bind to one or more residues of the amino acidsequence ENKFSAKRLPSTRLGTFLENRVNDFLRRQNHPESGEVTVRVVHASDKTVEVKPGMKARFVDSGEMAESFPYRTKALFAFEEIDGVDLCFFGMHVQEYGSDCPPPNQRRVYISYLDSVHFFRPKCLRTAVYHEILIGYLEYVKKLGYTTGHIWACPPSEGDDYIFHCHPPDQKIPKPKRLQEWYKKMLDKAVSERIVHDYKDIFKQATEDRLTSAKELPYFEGDFWPNVLEESIKELEQEEEERKREENTSNESTDVTKGDSKNAKKKNNKKTSKNKSSLSRGNKKKPGMPNVSNDLSQKLYATMEKHKEVFFVIRLIAGPAANSLPPIVDPDPLIPCDLMDGRDAFLTLARDKHLEFSSLRRAQWSTMCMLVELHTQSQD (amino acid residues 1285-1664 of UniProt No.Q09472 (SEQ ID NO:2)). In some embodiments, the CBP/EP300 bromodomaininhibitor does not inhibit the histone acetyltransferase (HAT) catalyticactivity of CBP and/or EP300.

Compounds that are CBP/EP300 bromodomain inhibitors are expected to haveimproved and/or distinct properties over other compounds, such as “HAT”inhibitor compounds. HAT inhibition is expected to result in a globalreduction in protein acetylation (histone and non-histone), likelyaffecting cell viability in a significant way. In some embodiments,CBP/EP300 bromodomain inhibition preserves the HAT activity of theseproteins while resulting in the reduction of transcriptional activity ofa relatively small subset of target genes.

In some embodiments, provided are methods of enhancing immune functionin an individual having cancer comprising administering an effectiveamount of any CBP/EP300 bromodomain inhibitors disclosed herein. In someembodiments of any of the methods, the CD8 T cells in the individualhave enhanced priming, activation, proliferation, and/or cytolyticactivity relative to prior to the administration of the CBP/EP300bromodomain inhibitor. In some embodiments, the number of CD8 T cells iselevated relative to prior to administration of the CBP/EP300bromodomain inhibitors. In some embodiments, the CD8 T cells havereduced levels of expression of one or more of the following biomarkers:IFNA17, IGFl, FSCNl, SUMO2, CIorf129, EIF2S2, TDGF1, AIDA, CCR4, CD160,MC4R, KRTAP2-2, MTIJP, OR4N2, KRTAP4-5, MTIL//MTIL, ILI3, LCEID,KIR2DL2, LOC158696, LIF, 1L28A, TAS2R13, CTLA4, and/or FOXP3 relative toprior to administration of the CBP/EP300 bromodomain inhibitor. In someembodiments, the CD8 T cells have reduced levels of expression of CD160and/or KIR2DL2 relative to prior to administration of the CBP/EP300bromodomain inhibitor.

In some embodiments of the methods of enhancing immune function, theenhanced immune function is characterized by Treg cells in theindividual (e.g., at the tumor site(s)) have reduced levels ofexpression of one or more of the following markers: 1L28A, GPR87,ANKRD37, CABLES1, RAPGEF2, TRIM69, MT1L//MT1L, FAM1138, FOXP3, CSF2,OCM2, GLIPR1, FGFBP2, CTLA4, CST7, GOLGA6L1, IFIT3, FAMl3A, APOD, AK2,CLDN1, HSD11B1, DNAJC12, PHEX, IL2, FOXD4L3, GNA15, ZBTB32, RDH10,OR52E5, CYP2A6, GZMH, CCL20, ADM, LOC100131541, RNF122, FAM36A, AMY2B,GPR183, MYOF, IL29, AIDA, SPRYI, ENOPH1, IL1RN, SLAMF1, PGM2L1, SSBP3,MMP23B, HISTlH3J, MYO1B, BENDS, S1PR1, CDK6, GPR56, ZC3HIZA, DOK5,DUSPI, CYB5R2, KCNAB2, LAG3, KLF10, GK, SHC4, IL12RB2, CD109, HAVCR2(TIM-3), LTA, FAM40B, HMGCSI, HSPAlA, ZNF705A, CMAH, KIF3A, CHN1,KBTBD8, TNF, MOP-1, RASGRP4, INSIG1, SLAMF7, ORl0H4, LPL, HIST1H2BJ,LIF, IGF1, ILl8RAP, OR52N4, OR1D2, CCR4, CXCR5, IL1R1, MICAL2, NRNl,PICALM, B3GNT5, IFI44L, CXCR3, ICOS, IFIT2, NCR3, HSPA1B, CD80, GNG2,C7orf68, GPRl71, RPSl0P7, IL23A, LOC283174, PLK2, EMP1, FNBP1L, CD226,RBMS3, IL23R, PTGER4, GZMB, F5, and/or HIST1H2BK relative to prior toadministration of CBP/EP300 bromodomain inhibitor. In some embodiments,the Treg cell biomarker is one or more of LAG3, CTLA4, and/or FOXP3. Insome embodiments of the methods of enhancing immune function, theenhanced immune function is characterized by enhanced naive T cellresponsiveness to CD3/CD28 stimulation in the presence of Treg cells. Insome embodiments, the CD8 T cell priming is characterized by increased Tcell proliferation and/or enhanced cytolytic activity in CD8 T cells. Insome embodiments, the CD8 T cell activation is characterized by anelevated frequency of T-IFN⁺ CD8 T cells. In some embodiments, the CD8 Tcell is an antigen-specific T-cell. In some embodiments, the immuneevasion is inhibited.

In some embodiments, the methods provided herein are useful in treatingconditions where enhanced immunogenicity is desired such as increasingtumor immunogenicity for the treatment of cancer. For example, providedherein are CBP/EP300 bromodomain inhibitors for use to enhance T-cellfunction to upregulate cell-mediated immune responses and for thetreatment of T cell dysfunctional disorders, tumor immunity. In someembodiments, the CBP/EP300 bromodomain inhibitors promote anti-tumorimmunity by inhibiting the suppressive function of regulatory T (Treg)cells and/or relieving T cell exhaustion on chronically stimulated CD8⁺T cells. CBP/EP300 bromodomain inhibitors are further useful in reducingFOXP3 expression during extra-thymic Treg cell differentiation.Continual FOXP3 expression is essential to maintain suppressive activityin Treg cells. In some embodiments, reduced FOXP3 expression throughCBP/EP300 bromodomain inhibition impairs Treg cells suppressive activityand promotes tumor antiimmunity. Treg cells are highly enriched intumors derived from multiple cancer indications, including melanoma,NSCLC, renal, ovarian, colon, pancreatic, hepatocellular, and breastcancer. In a subset of these indications, increased intratumoral Tregcell densities are associated with poor patient prognosis. Theseindications include NSCLC, ovarian, pancreatic, hepatocellular, andbreast cancer. CBP/EP300 bromodomain inhibitors are predicted to impairintratumoral Treg cell function in these cancer indications to enhanceeffector T cell activity. In other embodiments, the CBP/EP300bromodomain inhibitors may be used to treat infectious diseases, wheresome pathogens may have evolved to manipulate regulatory T (Treg) cellsto immunosuppress the host to ensure survival, such as in retrovialinfections (e.g., HIV), mycobacterial infections (e.g., tuberculosis),and parasitic infections (e.g., Leishmania and malaria).

In some embodiments, the methods provided herein are useful in treatinga CBP and/or EP300-mediated disorder involving fibrosis. In someembodiments, the CBP and/or EP300-mediated disorder is a fibroticdisease. Certain fibrotic diseases may include, for example, pulmonaryfibrosis, silicosis, cystic fibrosis, renal fibrosis, liver fibrosis,liver cirrhosis, primary sclerosing cholangitis, primary biliarycirrhosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis,retroperitoneal fibrosis, progressive massive fibrosis, nephrogenicsystemic fibrosis, Crohn's disease, keloid, myocardial infarction,systemic sclerosis or arthro fibrosis.

In other embodiments, the CBP and/or EP300-mediated disorder is afibrotic lung disease. Fibrotic lung diseases may include, for example,idiopathic pulmonary fibrosis, fibrotic interstitial lung disease,interstitial pneumonia, fibrotic variant of non-specific interstitialpneumonia, cystic fibrosis, lung fibrosis, chronic obstructive pulmonarylung disease (COPD), or pulmonary arterial hypertension. In certainembodiments, the fibrotic lung disease is idiopathic pulmonary fibrosis.

CBP and/or EP300-Mediated Disorders

A “CBP and/or EP300-mediated disorder” is characterized by theparticipation of the bromodomains of CBP and/or EP300 in the inception,manifestation of one or more symptoms or disease markers, severity, orprogression of a disorder. In one embodiment the bromodomain-mediateddisorder is a CBP bromodomain-mediated disorder. In one embodiment thebromodomain-mediated disorder is an EP300 bromodomain-mediated disorder.

CBP and/or EP300 bromodomain-mediated disorders include cancers,including, but not limited to acoustic neuroma, acute leukemia, acutelymphocytic leukemia, acute myelocytic leukemia (monocytic,myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocyticand promyelocytic), acute T-cell leukemia, basal cell carcinoma, bileduct carcinoma, bladder cancer, brain cancer, breast cancer,bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma,choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronicmyelocytic (granulocytic) leukemia, chronic myelogenous leukemia, coloncancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,diffuse large B-cell lymphoma, dysproliferative changes (dysplasias andmetaplasias), embryonal carcinoma, endometrial cancer,endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia,esophageal cancer, estrogen-receptor positive breast cancer, essentialthrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germcell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chaindisease, hemangioblastoma, hepatoma, hepatocellular cancer, hormoneinsensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lungcancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblasticleukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma,meningioma, mesothelioma, multiple myeloma, myelogenous leukemia,myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC),non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenicsarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas,papillary carcinoma, pinealoma, polycythemia vera, prostate cancer,rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma,sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small celllung carcinoma, solid tumors (carcinomas and sarcomas), small cell lungcancer, stomach cancer, squamous cell carcinoma, synovioma, sweat glandcarcinoma, thyroid cancer, Waldenstr6m's macroglobulinemia, testiculartumors, uterine cancer and Wilms' tumor.

In certain embodiments, the cancer is lung cancer, breast cancer,pancreatic cancer, colorectal cancer, and/or melanoma. In certainembodiments, the cancer is lung. In certain embodiments, the lung canceris NSCLC. In certain embodiments, the cancer is breast cancer.

In certain embodiments, the cancer is melanoma.

CBP and/or EP300-mediated disorders also include inflammatory diseases,inflammatory conditions, and autoimmune diseases, including, but notlimited to: Addison's disease, acute gout, ankylosing spondylitis,asthma, atherosclerosis, Behcet's disease, bullous skin diseases,chronic obstructive pulmonary disease (COPD), Crohn's disease,dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis,hypophysitis, inflammatory bowel disease, Kawasaki disease, lupusnephritis, multiple sclerosis, myocarditis, myositis, nephritis, organtransplant rejection, osteoarthritis, pancreatitis, pericarditis,Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis,psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosingcholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis,toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis,vitiligo, vasculitis, and Wegener's granulomatosis.

CBP and/or EP300-mediated disorders also include AIDS; chronic kidneydiseases, including, but are not limited to diabetic nephropathy,hypertensive nephropathy, HIV-associated nephropathy,glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmentalglomerulosclerosis, membranous glomerulonephritis, minimal changedisease, polycystic kidney disease and tubular interstitial nephritis;acute kidney injury or disease or condition including, but are notlimited to ischemia-reperfusion induced, cardiac and major surgeryinduced, percutaneous coronary intervention induced, radio-contrastagent induced, sepsis induced, pneumonia induced, and drug toxicityinduced; obesity; dyslipidemia; hypercholesterolemia; Alzheimer'sdisease; metabolic syndrome; hepatic steatosis; type II diabetes;insulin resistance; and diabetic retinopathy.

CBP and/or EP300 inhibitors may also be used to provide malecontraception.

CBP and/or EP300-mediated disorders also include fibrotic diseases.Certain fibrotic diseases may include, for example, pulmonary fibrosis,silicosis, cystic fibrosis, renal fibrosis, liver fibrosis, livercirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis,endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis,retroperitoneal fibrosis, progressive massive fibrosis, nephrogenicsystemic fibrosis, Crohn's disease, keloid, myocardial infarction,systemic sclerosis or arthro fibrosis.

CBP and/or EP300-mediated disorders also include fibrotic lung diseases.Fibrotic lung diseases may include, for example, idiopathic pulmonaryfibrosis, fibrotic interstitial lung disease, interstitial pneumonia,fibrotic variant of non-specific interstitial pneumonia, cysticfibrosis, lung fibrosis, chronic obstructive pulmonary lung disease(COPD), or pulmonary arterial hypertension. In certain embodiments, thefibrotic lung disease is idiopathic pulmonary fibrosis.

Co-Administration of Compounds and Other Agents

The compounds of formula (I) or salts thereof may be employed alone orin combination with other agents for treatment. For example, the secondagent of the pharmaceutical combination formulation or dosing regimenmay have complementary activities to the compound of formula (I) suchthat they do not adversely affect each other. The compounds may beadministered together in a unitary pharmaceutical composition orseparately. In one embodiment a compound or a pharmaceuticallyacceptable salt can be co-administered with a cytotoxic agent to treatproliferative diseases and cancer.

The term “co-administering” refers to either simultaneousadministration, or any manner of separate sequential administration, ofa compound of formula (I) or a salt thereof, and a further activepharmaceutical ingredient or ingredients, including cytotoxic agents andradiation treatment. If the administration is not simultaneous, thecompounds are administered in a close time proximity to each other.Furthermore, it does not matter if the compounds are administered in thesame dosage form, e.g. one compound may be administered topically andanother compound may be administered orally.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of formula (I),an additional therapeutic agent, and a pharmaceutically acceptablecarrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. In certainembodiments, compositions of this invention are formulated such that adosage of between 0.01-100 mg/kg body weight/day of an inventive can beadministered.

Typically, any agent that has activity against a disease or conditionbeing treated may be co-administered. Examples of such agents can befound in Cancer Principles and Practice of Oncology by V. T. Devita andS. Hellman (editors), 6^(th) edition (Feb. 15, 2001), LippincottWilliams & Wilkins Publishers. A person of ordinary skill in the artwould be able to discern which combinations of agents would be usefulbased on the particular characteristics of the drugs and the diseaseinvolved.

In one embodiment, the treatment method includes the co-administrationof a compound of formula (I) or a pharmaceutically acceptable saltthereof and at least one cytotoxic agent. The term “cytotoxic agent” asused herein refers to a substance that inhibits or prevents a cellularfunction and/or causes cell death or destruction. Cytotoxic agentsinclude, but are not limited to, radioactive isotopes (e.g., At²¹¹,I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactiveisotopes of Lu); chemotherapeutic agents; growth inhibitory agents;enzymes and fragments thereof such as nucleolytic enzymes; and toxinssuch as small molecule toxins or enzymatically active toxins ofbacterial, fungal, plant or animal origin, including fragments and/orvariants thereof.

Exemplary cytotoxic agents can be selected from anti-microtubule agents,platinum coordination complexes, alkylating agents, antibiotic agents,topoisomerase II inhibitors, antimetabolites, topoisomerase Iinhibitors, hormones and hormonal analogues, signal transduction pathwayinhibitors, non-receptor tyrosine kinase angiogenesis inhibitors,immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A;inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors;HDAC inhibitors, proteasome inhibitors; and inhibitors of cancermetabolism.

“Chemotherapeutic agent” includes chemical compounds useful in thetreatment of cancer. Examples of chemotherapeutic agents includeerlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®,Millennium Pharm.), disulfiram, epigallocatechin gallate,salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol,lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca),sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinibmesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis),oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin,Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016,Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, BayerLabs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents suchas thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (includingtopotecan and irinotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);adrenocorticosteroids (including prednisone and prednisolone);cyproterone acetate; 5α-reductases including finasteride anddutasteride); vorinostat, romidepsin, panobinostat, valproic acid,mocetinostat dolastatin; aldesleukin, talc duocarmycin (including thesynthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; asarcodictyin; spongistatin; nitrogen mustards such as chlorambucil,chlomaphazine, chlorophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine,nimustine, and ranimnustine; antibiotics such as the enediyneantibiotics (e.g., calicheamicin, especially calicheamicin γ1I andcalicheamicin ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186);dynemicin, including dynemicin A; bisphosphonates, such as clodronate;an esperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE®(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR®(gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinumanalogs such as cisplatin and carboplatin; vinblastine; etoposide(VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE®(vinorelbine); novantrone; teniposide; edatrexate; daunomycin;aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomeraseinhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such asretinoic acid; and pharmaceutically acceptable salts, acids andderivatives of any of the above.

Chemotherapeutic agent also includes (i) anti-hormonal agents that actto regulate or inhibit hormone action on tumors such as anti-estrogensand selective estrogen receptor modulators (SERMs), including, forexample, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene,droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene,LY117018, onapristone, and FARESTON® (toremifine citrate); (ii)aromatase inhibitors that inhibit the enzyme aromatase, which regulatesestrogen production in the adrenal glands, such as, for example,4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate),AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR®(vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole;AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide and goserelin; buserelin, tripterelin,medroxyprogesterone acetate, diethylstilbestrol, premarin,fluoxymesterone, all transretionic acid, fenretinide, as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors; (v) lipid kinase inhibitors; (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, suchas, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKIN®, rIL-2; a topoisomerase 1 inhibitorsuch as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceuticallyacceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes antibodies such as alemtuzumab(Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®,Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®,Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech),trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), andthe antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).Additional humanized monoclonal antibodies with therapeutic potential asagents in combination with the compounds of the invention include:apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine,cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab,cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab,felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin,ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab,motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab,numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab,pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab,reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab,sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan,tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab,tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab,ustekinumab, visilizumab, and the anti-interleukin-12 (ABT-874/J695,Wyeth Research and Abbott Laboratories) which is a recombinantexclusively human-sequence, full-length IgG₁ λ antibody geneticallymodified to recognize interleukin-12 p40 protein.

Chemotherapeutic agent also includes “EGFR inhibitors,” which refers tocompounds that bind to or otherwise interact directly with EGFR andprevent or reduce its signaling activity, and is alternatively referredto as an “EGFR antagonist.” Examples of such agents include antibodiesand small molecules that bind to EGFR. Examples of antibodies which bindto EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507),MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No.4,943,533, Mendelsohn et al.) and variants thereof, such as chimerized225 (C225 or Cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see, WO96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targetedantibody (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat.No. 5,212,290); humanized and chimeric antibodies that bind EGFR asdescribed in U.S. Pat. No. 5,891,996; and human antibodies that bindEGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen);EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996));EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR thatcompetes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); humanEGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known asE1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6. 3 and E7.6. 3 and described inU.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanizedmAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). Theanti-EGFR antibody may be conjugated with a cytotoxic agent, thusgenerating an immunoconjugate (see, e.g., EP659,439A2, Merck PatentGmbH). EGFR antagonists include small molecules such as compoundsdescribed in U.S. Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307,5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726,6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459,6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, aswell as the following PCT publications: WO98/14451, WO98/50038,WO99/09016, and WO99/24037. Particular small molecule EGFR antagonistsinclude OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSIPharmaceuticals); PD 183805 (CI 1033, 2-propenamide,N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-,dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®)4-(3′-Chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline,AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline,Zeneca); BIBX-1382(N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine,Boehringer Ingelheim); PKI-166((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol);(R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine);CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide);EKB-569(N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide)(Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 orN-[3-chloro-4-[(3 fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

Chemotherapeutic agents also include “tyrosine kinase inhibitors”including the EGFR-targeted drugs noted in the preceding paragraph;small molecule HER2 tyrosine kinase inhibitor such as TAK165 availablefrom Takeda; CP-724,714, an oral selective inhibitor of the ErbB2receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such asEKB-569 (available from Wyeth) which preferentially binds EGFR butinhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016;available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinaseinhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such ascanertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisenseagent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1signaling; non-HER targeted TK inhibitors such as imatinib mesylate(GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosinekinase inhibitors such as sunitinib (SUTENT®, available from Pfizer);VEGF receptor tyrosine kinase inhibitors such as vatalanib(PTK787/ZK222584, available from Novartis/Schering AG); MAPKextracellular regulated kinase I inhibitor CI-1040 (available fromPharmacia); quinazolines, such as PD 153035,4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines,such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines,4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloylmethane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containingnitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules(e.g. those that bind to HER-encoding nucleic acid); quinoxalines (U.S.Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); ZD6474(Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors suchas CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinibmesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo SmithKline);CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474(AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone),rapamycin (sirolimus, RAPAMUNE®); or as described in any of thefollowing patent publications: U.S. Pat. No. 5,804,396; WO 1999/09016(American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983(Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (WarnerLambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

Chemotherapeutic agents also include dexamethasone, interferons,colchicine, metoprine, cyclosporine, amphotericin, metronidazole,alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide,asparaginase, BCG live, bevacuzimab, bexarotene, cladribine,clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa,elotinib, filgrastim, histrelin acetate, ibritumomab, interferonalfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna,methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, plicamycin, porfimer sodium, quinacrine,rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene,tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, andpharmaceutically acceptable salts thereof.

Chemotherapeutic agents also include hydrocortisone, hydrocortisoneacetate, cortisone acetate, tixocortol pivalate, triamcinoloneacetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide,desonide, fluocinonide, fluocinolone acetonide, betamethasone,betamethasone sodium phosphate, dexamethasone, dexamethasone sodiumphosphate, fluocortolone, hydrocortisone-17-butyrate,hydrocortisone-17-valerate, aclometasone dipropionate, betamethasonevalerate, betamethasone dipropionate, prednicarbate,clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolonecaproate, fluocortolone pivalate and fluprednidene acetate; immuneselective anti-inflammatory peptides (ImSAIDs) such asphenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG)(IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such asazathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts,hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumornecrosis factor alpha (TNFα) blockers such as etanercept (Enbrel),infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia),golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra(Kineret), T cell costimulation blockers such as abatacept (Orencia),Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®);Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha(IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such asrhuMAb Beta7; IgE pathway blockers such as Anti-M1 prime; Secretedhomotrimeric LTa3 and membrane bound heterotrimer LTa1/β2 blockers suchas Anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At²¹¹,I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactiveisotopes of Lu); miscellaneous investigational agents such asthioplatin, PS-341, phenylbutyrate, ET-18-OCH₃, or famesyl transferaseinhibitors (L-739749, L-744832); polyphenols such as quercetin,resveratrol, piceatannol, epigallocatechine gallate, theaflavins,flavanols, procyanidins, betulinic acid and derivatives thereof;autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol(dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinicacid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin);podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®);bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®),etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®),alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), orrisedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R);vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g.celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779;tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitor such asoblimersen sodium (GENASENSE®); pixantrone; famesyltransferaseinhibitors such as lonafamib (SCH 6636, SARASAR™); and pharmaceuticallyacceptable salts, acids or derivatives of any of the above; as well ascombinations of two or more of the above such as CHOP, an abbreviationfor a combined therapy of cyclophosphamide, doxorubicin, vincristine,and prednisolone; and FOLFOX, an abbreviation for a treatment regimenwith oxaliplatin (ELOXATIN™) combined with 5-FU and leucovorin.

Chemotherapeutic agents also include non-steroidal anti-inflammatorydrugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDsinclude non-selective inhibitors of the enzyme cyclooxygenase. Specificexamples of NSAIDs include aspirin, propionic acid derivatives such asibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen,acetic acid derivatives such as indomethacin, sulindac, etodolac,diclofenac, enolic acid derivatives such as piroxicam, meloxicam,tenoxicam, droxicam, lomoxicam and isoxicam, fenamic acid derivativessuch as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamicacid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib,parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicatedfor the symptomatic relief of conditions such as rheumatoid arthritis,osteoarthritis, inflammatory arthropathies, ankylosing spondylitis,psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea,metastatic bone pain, headache and migraine, postoperative pain,mild-to-moderate pain due to inflammation and tissue injury, pyrexia,ileus, and renal colic.

In certain embodiments, chemotherapeutic agents include, but are notlimited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide,fluorouracil, topotecan, interferons, platinum derivatives, taxanes(e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine),anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g.,etoposide), cisplatin, an mTOR inhibitor (e.g., a rapamycin),methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents (e.g., chlorambucil), 5-fluorouracil, campthothecin,cisplatin, metronidazole, and imatinib mesylate, among others. In otherembodiments, a compound of the present invention is administered incombination with a biologic agent, such as bevacizumab or panitumumab.

In certain embodiments, compounds of the present invention, or apharmaceutically acceptable composition thereof, are administered incombination with an antiproliferative or chemotherapeutic agent selectedfrom any one or more of abarelix, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenictrioxide, asparaginase, azacitidine, BCG live, bevacuzimab,fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone,capecitabine, camptothecin, carboplatin, carmustine, cetuximab,chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine,dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane,docetaxel, doxorubicin (neutral), doxorubicin hydrochloride,dromostanolone propionate, epirubicin, epoetin alfa, elotinib,estramustine, etoposide phosphate, etoposide, exemestane, filgrastim,floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine,gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea,ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferonalfa-2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole,leucovorin, leuprolide acetate, levamisole, lomustine, megestrolacetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim,sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen,temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,zoledronate, or zoledronic acid.

Chemotherapeutic agents also include treatments for Alzheimer's Diseasesuch as donepezil hydrochloride and rivastigmine; treatments forParkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole,pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine;agents for treating multiple sclerosis (MS) such as beta interferon(e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone;treatments for asthma such as albuterol and montelukast sodium; agentsfor treating schizophrenia such as zyprexa, risperdal, seroquel, andhaloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; and agentsfor treating immunodeficiency disorders such as gamma globulin.

Additionally, chemotherapeutic agents include pharmaceuticallyacceptable salts, acids or derivatives of any of chemotherapeuticagents, described herein, as well as combinations of two or more ofthem.

In another embodiment, provided are methods of using CBP/EP300bromodomain inhibitors to treat and/or delay progression of cancer incombination with a PD-1 axis binding antagonist. Further provided hereinare methods of enhancing immune function in an individual having cancercomprising administering to the individual an effective amount of aCBP/EP300 bromodomain inhibitor and an effective amount of a PD-1 axisbinding antagonist. A PD-1 axis binding antagonist includes a PD-1binding antagonist, a PD-L1 binding antagonist and a PD-L2 bindingantagonist.

The term “PD-1 axis binding antagonist” is a molecule that inhibits theinteraction of a PD-1 axis binding partner with either one or more ofits binding partner, so as to remove T-cell dysfunction resulting fromsignaling on the PD-1 signaling axis—with a result being to restore orenhance T-cell function (e.g., proliferation, cytokine production,target cell killing). As used herein, a PD-1 axis binding antagonistincludes a PD-1 binding antagonist, a PD-L1 binding antagonist and aPD-L2 binding antagonist.

The term “PD-1 binding antagonists” is a molecule that decreases,blocks, inhibits, abrogates or interferes with signal transductionresulting from the interaction of PD-1 with one or more of its bindingpartners, such as PDL1, PDL2. In some embodiments, the PD-1 bindingantagonist is a molecule that inhibits the binding of PD-1 to itsbinding partners. In a specific aspect, the PD-1 binding antagonistinhibits the binding of PD-1 to PDL1 and/or PDL2. For example, PD-1binding antagonists include anti-PD-1 antibodies, antigen bindingfragments thereof, immunoadhesins, fusion proteins, oligopeptides andother molecules that decrease, block, inhibit, abrogate or interferewith signal transduction resulting from the interaction of PD-1 withPDL1 and/or PDL2. In one embodiment, a PD-1 binding antagonist reducesthe negative co-stimulatory signal mediated by or through cell surfaceproteins expressed on T lymphocytes mediated signaling through PD-1 soas render a dysfunctional T-cell less dysfunctional (e.g., enhancingeffector responses to antigen recognition). In some embodiments, thePD-1 binding antagonist is an anti-PD-1 antibody. In a specific aspect,a PD-1 binding antagonist is nivolumab described herein (also known asMDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO®). In anotherspecific aspect, a PD-1 binding antagonist is pembrolizumab describedherein (also known as MK-3475, Merck 3475, KEYTRUDA®, and SCH-900475).In another specific aspect, a PD-1 binding antagonist is CT-011described herein (also known as hBAT or hBAT-1). In yet another specificaspect, a PD-1 binding antagonist is AMP-224 (also known as B7-DCIg)described herein.

The term “PDL1 binding antagonists” is a molecule that decreases,blocks, inhibits, abrogates or interferes with signal transductionresulting from the interaction of PDL1 with either one or more of itsbinding partners, such as PD-1, B7-1. In some embodiments, a PDL1binding antagonist is a molecule that inhibits the binding of PDL1 toits binding partners. In a specific aspect, the PDL1 binding antagonistinhibits binding of PDL1 to PD-1 and/or B7-1. In some embodiments, thePDL1 binding antagonists include anti-PDL1 antibodies, antigen bindingfragments thereof, immunoadhesins, fusion proteins, oligopeptides andother molecules that decrease, block, inhibit, abrogate or interferewith signal transduction resulting from the interaction of PDL1 with oneor more of its binding partners, such as PD-1, B7-1. In one embodiment,a PDL1 binding antagonist reduces the negative co-stimulatory signalmediated by or through cell surface proteins expressed on T lymphocytesmediated signaling through PDL1 so as to render a dysfunctional T-cellless dysfunctional (e.g., enhancing effector responses to antigenrecognition). In some embodiments, a PDL1 binding antagonist is ananti-PDL1 antibody. In a specific aspect, an anti-PDL1 antibody isYW243.55.S70 described herein. In another specific aspect, an anti-PDL1antibody is MDX-1105 described herein (also known as BMS-936559). Instill another specific aspect, an anti-PDL1 antibody is MPDL3280Adescribed herein. In still another specific aspect, an anti-PDL1antibody is MEDI4736 described herein.

The term “PDL2 binding antagonists” is a molecule that decreases,blocks, inhibits, abrogates or interferes with signal transductionresulting from the interaction of PD-L2 with either one or more of itsbinding partners, such as PD-1. In some embodiments, a PD-L2 bindingantagonist is a molecule that inhibits the binding of PD-L2 to itsbinding partners. In a specific aspect, the PD-L2 binding antagonistinhibits binding of PD-L2 to PD-1. In some embodiments, the PD-L2antagonists include anti-PD-L2 antibodies, antigen binding fragmentsthereof, immunoadhesins, fusion proteins, oligopeptides and othermolecules that decrease, block, inhibit, abrogate or interfere withsignal transduction resulting from the interaction of PD-L2 with eitherone or more of its binding partners, such as PD-1. In one embodiment, aPD-L2 binding antagonist reduces the negative co-stimulatory signalmediated by or through cell surface proteins expressed on T lymphocytesmediated signaling through PD-L2 so as render a dysfunctional T-cellless dysfunctional (e.g., enhancing effector responses to antigenrecognition). In some embodiments, a PD-L2 binding antagonist is animmunoadhesin.

Alternative names for “PD-1” include CD279 and SLEB2. Alternative namesfor “PD-L1” include B7-H 1, B7-4, CD274, and B7-H. Alternative names for“PD-L2” include B7-DC, Btdc, and CD273. In some embodiments, PD-1,PD-L1, and PD-L2 are human PD-1, PD-L1 and PD-L2. In some embodiments,the PD-1 binding antagonist is a molecule that inhibits the binding ofPD-1 to its ligand binding partners. In a specific aspect the PD-1ligand binding partners are PD-L1 and/or PD-L2. In another embodiment, aPD-L1 binding antagonist is a molecule that inhibits the binding ofPD-L1 to its binding partners. In a specific aspect, PD-L1 bindingpartners are PD-1 and/or B7-1. In another embodiment, the PD-L2 bindingantagonist is a molecule that inhibits the binding of PD-L2 to itsbinding partners. In a specific aspect, a PD-L2 binding partner is PD-1.The antagonist may be an antibody, an antigen binding fragment thereof,an immunoadhesin, a fusion protein, or oligopeptide. In some embodiment,the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., a humanantibody, a humanized antibody, or a chimeric antibody). In someembodiments, the anti-PD-1 antibody is selected from the groupconsisting of MDX-1 106, Merck 3475 (also known as: pembrolizumab,lambrolizumab, or MK-3475), nivolumab (BMS-936558), CT-011, andMPDL3280A. In some embodiments, the PD-1 binding antagonist is animmunoadhesin (e.g., an immunoadhesin comprising an extracellular orPD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g.,an Fc region of an immunoglobulin sequence). In some embodiments, thePD-1 binding antagonist is AMP-224. In some embodiments, the PD-L1binding antagonist is anti-PD-L1 antibody. In some embodiments, theanti-PD-L1 binding antagonist is selected from the group consisting ofYW243.55.S70, MPDL3280A and MDX-1 105. MDX-1 105, also known asBMS-936559, is an anti-PD-L1 antibody described in WO2007/005874.Antibody YW243.55.S70 (heavy and light chain variable region sequencesshown in SEQ ID Nos. 20 and 21, respectively) is an anti-PD-L1 describedin WO 2010/077634 A1. MDX-1 106, also known as MDX-1 106-04, ONO-4538 orBMS-936558, is an anti-PD-1 antibody described in WO2006/121168. Merck3745, also known as MK-3475 or SCH-900475, is an anti-PD-1 antibodydescribed in WO2009/114335. CT-011, also known as hBAT or hBAT-1, is ananti-PD-1 antibody described in WO2009/101611. AMP-224, also known asB7-DCIg, is a PD-L2-Fc fusion soluble receptor described inWO2010/027827 and WO201 1/066342. In some embodiments, the anti-PD-1antibody is MDX-1 106. Alternative names for “MDX-1106” include MDX-1106-04, ONO-4538, BMS-936558 or Nivolumab. In some embodiments, theanti-PD-1 antibody is Nivolumab (CAS Registry Number: 946414-94-4). Insome embodiments, the cancer is melanoma, NSCLC, and renal cellcarcinoma.

For treating an inflammatory disease or an autoimmune disease, acompound of formula (I) or a pharmaceutically acceptable salt thereofmay be co-administered with methotrexate, tofacitinib, 6-mercaptopurine,azathioprine sulphasalazine, mesalazine, olsalazinechloroquinine/hydroxychloroquinine, penicillamine, aurothiomalate(intramuscular and oral), azathioprine, cochicine, corticosteroids(oral, inhaled, and local injection), a beta-2 adrenoreceptor agonist(salbutamol, terbutaline, salmeteral), a xanthine (theophylline,aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium andoxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil,leflunomide, an NSAID (e.g. ibuprofen), a corticosteroid (e. g.prednisolone), a phosphodiesterase inhibitor, an adensosine agonist, anantithrombotic agent, a complement inhibitor, an adrenergic agent, anagent that interferes with signalling by proinflammatory cytokines suchas TNF or IL-1 (e.g., a NIK, IKK, p38 or MAP kinase inhibitor), an IL-1converting enzyme inhibitor, a T-cell signalling inhibitor (e.g. akinase inhibitor), a metalloproteinase inhibitor, sulfasalazine, a6-mercaptopurine, an angiotensin converting enzyme inhibitor, a solublecytokine receptor (e.g. soluble p55 or p75 TNF receptors and thederivatives p75TNFRigG (etanercept) and p55TNFRigG (Lenercept), siL-1RI,siL-1RII, siL-6R), an antiinflammatory cytokine (e.g. IL-4, IL-l 0,IL-11, IL-13 and TGF), celecoxib, folic acid, hydroxychloroquinesulfate, rofecoxib, etanercept, infliximab, adalimumab, certolizumab,tocilizumab, abatacept, naproxen, valdecoxib, sulfasalazine,methylprednisolone, meloxicam, methylprednisolone acetate, gold sodiumthiomalate, aspirin, triamcinolone acetonide, propoxyphenenapsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac,diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodonebitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra,tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine,acetaminophen, alendronate sodium, prednisolone, cortisone,betamethasone, morphine sulfate, lidocaine hydrochloride, indomethacin,glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodoneHCVacetaminophen, olopatadine HCl misoprostol, naproxen sodium,omeprazole, cyclophosphamide, rituximab, IL-l TRAP, MRA, CTLA4-IG, IL-18BP, anti-IL-12, Anti-IL1S, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740,Roflumilast, IC-485, CDC-801, S1PI agonists (such as FTY720), a PKCfamily inhibitor (e.g. Ruboxistaurin or AEB-071) or Mesopram. In certainembodiments, a compound of formula (I) or a pharmaceutically acceptablesalt thereof may be co-administered with methotrexate or leflunomide. Inmoderate or severe Rheumatoid arthritis cases, a compound of formula (I)or a pharmaceutically acceptable salt thereof may be co-administeredwith cyclosporine and anti-TNF antibodies as noted above. A compound offormula (I) or a pharmaceutically acceptable salt thereof may also beco-administered with: budenoside; epidermal growth factor; acorticosteroid; cyclosporin, sulfasalazine; an aminosalicylate;6-mercaptopurine; azathioprine; metronidazole; a lipoxygenase inhibitor;mesalamine; olsalazine; balsalazide; an antioxidant; a thromboxaneinhibitor; an IL-1 receptor antagonist; an anti-IL-1 monoclonalantibody; an anti-IL-6 monoclonal antibody; a growth factor; an elastaseinhibitor; a pyridinyl-imidazole compound; an antibody to or antagonistof other human cytokines or growth factors (e.g. TNF, LT, IL-1, IL-2,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, andPDGF); a cell surface molecule (e.g. CD2, CD3, CD4, CD8, CD25, CD28,CD30, CD40, CD45, CD69, or CD90 or their ligands); methotrexate;cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide; anNSAID (e.g. ibuprofen); a corticosteroid (e.g. prednisolone); aphosphodiesterase inhibitor; an adenosine agonist; an antithromboticagent; a complement inhibitor; an adrenergic agent; an agent thatinterferes with signalling by proinflammatory cytokines such as TNF 5 orIL-1 (e.g. a NIK, IKK, or MAP kinase inhibitor); an IL-l convertingenzyme inhibitor; a TNF converting enzyme inhibitor; a T-cell signallinginhibitor such as kinase inhibitors; a metalloproteinase inhibitor;sulfasalazine; azathioprine; a 6-mercaptopurine; an angiotensinconverting enzyme inhibitor; a soluble cytokine receptor (e.g. solublep55 or p75 TNF receptors, siL-1RI, siL-1RII, siL-6R), and anantiinflammatory cytokine (e.g. IL-4, IL-l 0, IL-11, IL-13 or TGF).

For treating Crohn's disease, a compound of formula (I) or apharmaceutically acceptable salt thereof may be co-administered with aTNF antagonist (e.g. an anti-TNF antibody), D2E7 (adalimumab), CA2(infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG (etanercept)), ap55TNFRigG (LENERCEPT™) inhibitor, or a PDE4 inhibitor.

For treating inflammatory bowel disease, a compound of formula (I) or apharmaceutically acceptable salt thereof may be co-administered with acorticosteroid (e.g. budenoside or dexamethasone); sulfasalazine,5-aminosalicylic acid; olsalazine; an agent that interferes withsynthesis or action of proinflammatory cytokines such as IL-1 (e.g. anIL-l converting enzyme inhibitor or IL-lra); a T cell signalinginhibitor (e.g. a tyrosine kinase inhibitor); 6-mercaptopurine; IL-11;mesalamine; prednisone; azathioprine; mercaptopurine; infliximab;methylprednisolone sodium succinate; diphenoxylate/atrop sulfate;loperamide hydrochloride; methotrexate; omeprazole; folate;ciprofloxacin/dextrose-water; hydrocodone bitartrate/apap; tetracyclinehydrochloride; fluocinonide; metronidazole; thimerosal/boric acid;cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyaminesulfate; meperidine hydrochloride; midazolam hydrochloride; oxycodoneHCl/acetaminophen; promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab or interferon-gamma.

For treating multiple sclerosis, a compound of formula (I) or apharmaceutically acceptable salt thereof may be co-administered with acorticosteroid; prednisolone; methylprednisolone; azathioprine;cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine;tizanidine; interferon-la (AVONEX®; Biogen); interferon-1b (BETASERON®;Chiron/Berlex); interferon-n3) (Interferon Sciences/Fujimoto),interferon-(Alfa Wassermann/J&J), interferon 1A-IF (Serono/InhaleTherapeutics), Peginterferon 2b (Enzon/Schering-Plough), Copolymer 1(Cop-1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaricoxygen; intravenous immunoglobulin; cladribine; an antibody to orantagonist of other human cytokines or growth factors and theirreceptors (e.g. TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23,IL-15, IL-16, EMAP-II, GM-CSF, FGF, or PDGF).

For treating AIDS a compound of formula (I) or a pharmaceuticallyacceptable salt thereof may be co-administered with antibodies to cellsurface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28,CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. A compound offormula (I) or a pharmaceutically acceptable salt thereof may also beco-administered with methotrexate, cyclosporine, FK506, rapamycin,mycophenolate mofetil, leflunomide, an S1P1 agonist, an NSAID (e.g.ibuprofen), a corticosteroid (e.g. prednisolone), a phosphodiesteraseinhibitor, an adensosine agonist, an antithrombotic agent, a complementinhibitor, an adrenergic agent, an agent that interferes with signallingby proinflammatory cytokines such as TNF or IL-l (e.g., a NIK, IKK, p38or MAP kinase inhibitor), an IL-l converting enzyme inhibitor, a TACEinhibitor, a T-cell signaling inhibitor (e. g. a kinase inhibitor), ametalloproteinase inhibitor, sulfasalazine, azathioprine, a6-mercaptopurine, an angiotensin converting enzyme inhibitor, a solublecytokine receptor (e. g. soluble p55 or p75 TNF receptors, siL-1RI,siL-1RII, or siL-6R), or an antiinflammatory cytokine (e.g. IL-4, IL-l0, IL-13 or TGF).

A compound of formula (I) or a pharmaceutically acceptable salt thereofmay also be co-administered with agents, such as alemtuzumab,dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride,fampridine, glatiramer acetate, natalizumab, sinnabidol, immunokineNNS03, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778,calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD(cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, ananti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258(RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2, tiplimotide,a VLA-4 antagonist (e.g. TR-14035, VLA4 Ultrahaler, orAntegran-ELAN/Biogen), an interferon gamma antagonist, or an IL-4agonist.

For treating ankylosing spondylitis a compound of formula (I) or apharmaceutically acceptable salt thereof may be co-administered withibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin,diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate,azathioprine, minocyclin, prednisone, an anti-TNF antibody, D2E7(HUMIRA®), CA2 (infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG(ENBREL®), or p55TNFRigG (LENERCEPT®).

For treating asthma a compound of formula (I) or a pharmaceuticallyacceptable salt thereof may be co-administered with albuterol,salmeterol/fluticasone, montelukast sodium, fluticasone propionate,budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl,albuterol sulfate/ipratropium, prednisolone sodium phosphate,triamcinolone acetonide, beclomethasone dipropionate, ipratropiumbromide, azithromycin, pirbuterol acetate, prednisolone, theophyllineanhydrous, methylprednisolone sodium succinate, clarithromycin,zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillintrihydrate, flunisolide, cromolyn sodium, fexofenadine hydrochloride,flunisolide/menthol, amoxicillin/clavulanate, levofloxacin, guaifenesin,dexamethasone sodium phosphate, moxifloxacin HCl, doxycycline hyclate,guaifenesin/d-methorphan, p-ephedrine/cod/-chlorphenir, gatifloxacin,cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate,benzonatate, cephalexin, pe/hydrocodone/chlorphenir, cetirizineHCl/pseudoephed, phenylephrine/cod/promethazine, codeine/promethazine,cefprozil, dexamethasone, guaifenesin/pseudoephedrine,chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate,epinephrine, methylprednisolone, an anti-IL-13 antibody, ormetaproterenol sulfate.

For treating COPD a compound of formula (I) or a pharmaceuticallyacceptable salt thereof may be co-administered with albuterolsulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone,albuterol, salmeterol xinafoate, fluticasone propionate, prednisone,theophylline anhydrous, methylprednisolone sodium succinate, montelukastsodium, budesonide, formoterol fumarate, triamcinolone acetonide,levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate,levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillintrihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate,flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenolsulfate, methylprednisolone, mometasone furoate,p-ephedrine/cod/chlorphenir, pirbuterol acetate, p-ephedrine/loratadine,terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT,cilomilast, or roflumilast.

For treating psoriasis, a compound of formula (I) or a pharmaceuticallyacceptable salt thereof may be co-administered with calcipotriene,clobetasol propionate, triamcinolone acetonide, halobetasol propionate,tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented,fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate,mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisonevalerate, flurandrenolide, urea, betamethasone, clobetasolpropionate/emoll, fluticasone propionate, azithromycin, hydrocortisone,moisturizing formula, folic acid, desonide, pimecrolimus, coal tar,diflorasone diacetate, etanercept folate, lactic acid, methoxsalen,he/bismuth subgal/znox/resor, methylprednisolone acetate, prednisone,sunscreen, halcinonide, salicylic acid, anthralin, clocortolonepivalate, coal extract, coal tar/salicylic acid, coal tar/salicylicacid/sulfur, desoximetasone, diazepam, emollient,fluocinonide/emollient, mineral oil/castor oil/na lact, mineraloil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic acid,soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab,cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA,UVB, sulfasalazine, ABT-874 or ustekinamab.

For treating psoriatic arthritis, a compound of formula (I) or apharmaceutically acceptable salt thereof may be co-administered withmethotrexate, etanercept, rofecoxib, celecoxib, folic acid,sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (adalimumab), orefalizumab.

For treating lupus, a compound of formula (I) or a pharmaceuticallyacceptable salt thereof may be co-administered with an NSAID (e.g.diclofenac, naproxen, ibuprofen, piroxicam, or indomethacin); a COX2inhibitor (e.g. celecoxib, rofecoxib, or valdecoxib); an anti-malarial(e.g. hydroxychloroquine); a steroid (e.g. prednisone, prednisolone,budenoside, or dexamethasone); a cytotoxic (e.g. azathioprine,cyclophosphamide, mycophenolate mofetil, or methotrexate); an inhibitorof PDE4, or a purine synthesis inhibitor (e.g. Cellcept®). For example,a compound of formula (I) or a pharmaceutically acceptable salt thereofmay be co-administered with sulfasalazine, 5-aminosalicylic acid,olsalazine, Imuran®, an agent that interferes with the synthesis,production, or action of a proinflammatory cytokine (e.g. IL-l), or acaspase inhibitor (e.g. a IL-l converting enzyme inhibitor or IL-lra).

A compound of formula (I) or a pharmaceutically acceptable salt thereofmay also be co-administered with a T cell signaling inhibitor (e.g. atyrosine kinase inhibitor), or a molecule that targets T cell activation(e.g. CTLA-4-IgG, an anti-B7 family antibody, or an anti-PD-1 familyantibody).

A compound of formula (I) or a pharmaceutically acceptable salt thereofcan also be co-administered with an IL-11 antibody, an anti-cytokineantibody (e.g. fonotolizumab (anti-IFNg antibody)), or an anti-receptorreceptor antibodies (e.g. an anti-IL-6 receptor antibody or an antibodyto a B-cell surface molecule).

A compound of formula (I) or a pharmaceutically acceptable salt thereofcan also be co-administered with LJP 394 (abetimus), an agent thatdepletes or inactivates B-cells (e.g. Rituximab (anti-CD20 antibody) orlymphostat-B (anti-BlyS antibody)), a TNF antagonist (e.g. an anti-TNFantibody), D2E7 (adalimumab), CA2 (infliximab), CDP 571, a TNFR-Igconstruct, (p75TNFRigG (etanercept), or p55TNFRigG (LENERCEPT™).

A compound of formula (I) or a pharmaceutically acceptable salt thereofcan also be co-administered with one or more agents used in theprevention or treatment of AIDS: an HIV reverse transcriptase inhibitor,an HIV protease inhibitor, an immunomodulator, or another retroviraldrug. Examples of reverse transcriptase inhibitors include, but are notlimited to, abacavir, adefovir, didanosine, dipivoxil delavirdine,efavirenz, emtricitabine, lamivudine, nevirapine, rilpivirine,stavudine, tenofovir, zalcitabine, and zidovudine. Examples of proteaseinhibitors include, but are not limited to, amprenavir, atazanavir,darunavir, indinavir, fosamprenavir, lopinavir, nelfinavir, ritonavir,saquinavir, and tipranavir. Examples of other retroviral drugs include,but are not limited to, elvitegravir, enfuvirtide, maraviroc andraltegravir.

For treating type II diabetes, hepatic steatosis, insulin resistance,metabolic syndrome or a related disorder, a compound of formula (I) or apharmaceutically acceptable salt thereof may be co-administered withinsulin or insulins that have been modified to improve the duration ofaction in the body; agents that stimulate insulin secretion such asacetohexamide, chlorpropamide, glyburide, glimepiride, glipizide,glicazide, glycopyramide, gliquidone, rapaglinide, nataglinide,tolazamide or tolbutamide; agents that are glucagon-like peptideagonists such as exanatide, liraglutide or taspoglutide; agents thatinhibit dipeptidyl-peptidase IV such as vildagliptin, sitagliptin,saxagliptin, linagliptin, allogliptin or septagliptin; agents that bindto the peroxisome proliferator-activated receptor gamma such asrosiglitazone or pioglitazone; agents that decrease insulin resistancesuch as metformin; or agents that reduce glucose absorbance in the smallintestine such as acarbose, miglitol or voglibose.

For treating acute kidney disorders or a chronic kidney disease, acompound of formula (I) or a pharmaceutically acceptable salt thereofmay be co-administered with dopamine, a diuretic (e.g. furosemide),bumetanide, thiazide, mannitol, calcium gluconate, sodium bicarbonate,albuterol, paricalcitol, doxercalciferol, cinacalcet, or bardoxalonemethyl.

The amount of both the compound of formula (I) or salt thereof andadditional agent (in those compositions which comprise an additionaltherapeutic agent as described above) that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Incertain embodiments, compositions of this invention are formulated suchthat a dosage of between 0.01-100 mg/kg body weight/day of an inventivecan be administered.

The additional therapeutic agent and the compound of formula (I) may actsynergistically. Therefore, the amount of additional therapeutic agentin such compositions may be less than that required in a monotherapyutilizing only that therapeutic agent, or there may be fewer sideeffects for the patient given that a lower dose is used. In certainembodiments, in such compositions a dosage of between 0.01-1,000 μg/kgbody weight/day of the additional therapeutic agent can be administered.

Provided herein are methods of extending the duration of response to acytotoxic agent in an individual with cancer comprising administering tothe individual (a) an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof and (b) an effective amount ofthe cytotoxic agent.

In certain embodiments of any of the methods, the cytotoxic agent is atargeted therapy. In certain embodiments, the targeted therapy is one ormore of an EGFR antagonist, RAF inhibitor, and/or PI3K inhibitor.

In certain embodiments of any of the methods, the targeted therapy is anEGFR antagonist. In certain embodiments of any of the methods, the EGFRantagonist isN-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine and/or apharmaceutical acceptable salt thereof. In certain embodiments, the EGFRantagonist isN-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. Incertain embodiments, the EGFR antagonist isN-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-amine,di4-methylbenzenesulfonate or a pharmaceutically acceptable salt thereof(e.g., lapatinib).

In certain embodiments of any of the methods, targeted therapy is a RAFinhibitor. In certain embodiments, the RAF inhibitor is a BRAFinhibitor. In certain embodiments, the RAF inhibitor is a CRAFinhibitor.

In certain embodiments, the BRAF inhibitor is vemurafenib. In certainembodiments, the RAF inhibitor is3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamideor a pharmaceutically acceptable salt thereof (e.g., AZ628 (CAS#878739-06-1)).

In certain embodiments of any of the methods, the targeted therapy is aPI3K inhibitor.

In certain embodiments of any of the methods, the cytotoxic agent ischemotherapy. In certain embodiments of any of the methods, thechemotherapy is a taxane. In certain embodiments, the taxane ispaclitaxel. In certain embodiments, the taxane is docetaxel.

In certain embodiments of any of the methods, the cytotoxic agent is aplatinum agent. In certain embodiments, the platinum agent iscarboplatin. In certain embodiments, the platinum agent is cisplatin. Incertain embodiments of any of the methods, the cytotoxic agent is ataxane and a platinum agent. In certain embodiments, the taxane ispaclitaxel. In certain embodiments, the taxane is docetaxel. In certainembodiments, the platinum agent is carboplatin. In certain embodiments,the platinum agent is cisplatin.

In certain embodiments of any of the methods, the cytotoxic agent is avinca alkyloid. In certain embodiments, the vinca alkyloid isvinorelbine. In certain embodiments of any of the methods, thechemotherapy is a nucleoside analog. In certain embodiments, thenucleoside analog is gemcitabine.

In certain embodiments of any of the methods, the cytotoxic agent isradiotherapy.

In certain embodiments of any of the methods, the compound of formula(I) or a pharmaceutically acceptable salt thereof is concomitantlyadministered with the cytotoxic agent (e.g., targeted therapy,chemotherapy, and/or radiotherapy). In certain embodiments, the compoundof formula (I) or a pharmaceutically acceptable salt thereof isadministered prior to and/or concurrently with the cytotoxic agent(e.g., targeted therapy, chemotherapy, and/or radiotherapy).

Exemplification of Compounds of Formula (I)

As depicted in the Examples of Compounds of Formula (I), below, incertain exemplary embodiments, compounds of Formula (I) are preparedaccording to the following general procedures. It will be appreciatedthat, although the general methods depict the synthesis of certaincompounds of the present invention, the following general methods, andother methods known to one of ordinary skill in the art, can be appliedto all compounds and subclasses and species of each of these compounds,as described herein.

Compounds of formula (4) may be prepared by general synthetic methods asshown in Scheme 1.

Reaction between cyano-ketone (1) and hydrazine in a suitable solventsuch as ethanol at a temperature ranging from about room temperature toreflux and for a time varying from about 30 minutes to about 2 hours,can readily produce bicycle-pyrazole (2). The bromo pyrazole (3) can beformed by converting the amino pyrazole (2) using a nitrite such as, butnot limited to, isoamylnitrite, sodium nitrite, or tert-butyl nitriteand a copper salt such as, but not limited to, copper(II) bromide inorganic an solvent such as, but not limited to, acetonitrile at atemperature of about 20° C. to about 60° C. for a time of about 5 hours.The alkylation of pyrazole N¹ nitrogen of (2) can be carried out usingan alkyl iodide/bromide/mesylate/triflate in the presence of aninorganic base such as, but not limited to, sodium hydride or cesiumcarbonate in a suitable organic solvent such as, but not limited to,N,N-dimethylformamide (DMF) or tetrahydrofuran (THF) at a temperatureranging from about 0° C. to 120° C. and for a time varying from about 30minutes to about 16 hours to form compounds of formula (4).

Compounds of formula (8) and (11) may be prepared by general syntheticmethods as shown in Scheme 2.

Deprotection of N-tert-butoxycarbonyl (Boc) group using a protic acidsuch as, but not limited to, trifluoroacetic acid or hydrochloric acid,and subsequent N-acetylation using acetic anhydride in the presence of abase such as, but not limited to, triethylamine (TEA) can readily affordcompounds of formula (5). Compounds of formula (8) can be prepared fromthe bromide (5) upon treatment with aryl, heteroaryl or heterocyclicboronic acids or boronate esters (7) under palladium catalyst conditionssuch as, but not limited to, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of water and an inorganic basesuch as, but not limited to, sodium carbonate, potassium carbonate, orpotassium phosphate in an organic solvent such as, but not limited to,1,4-dioxane at an elevated temperature. Alternatively, reaction betweenbromide (5) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in thepresence of base such as, but not limited to, potassium acetate orpotassium 2-ethyl heanoate, under palladium catalyst conditions such as,but not limited to, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of an organic solvent such as, butnot limited to, 1,4-dioxane or dimethylformamide, can produce thecorresponding boronate ester that upon treatment with aryl, heteroarylor heterocyclic halides under the analogous palladium catalystconditions can also yield compounds of formula (8). To access compoundsof formula (11), Boc-protected (4) can be directly elaborated tocompounds of formula (9) using either coupling procedure describedabove. Subjection of piperidine (9) to the protic conditions describedabove, followed by treatment with a base such as, but not limited to,triethylamine (TEA), and urea (10) provides compounds of formula (11).

Compounds of formula (8a) and (11a) may be prepared by general syntheticmethods as shown in Scheme 3.

Deprotection of N-tert-butoxycarbonyl (Boc) group using a protic acidsuch as, but not limited to, trifluoroacetic acid or hydrochloric acid,and subsequent N-acetylation using acetic anhydride in the presence of abase such as, but not limited to, triethylamine (TEA) can readily affordcompounds of formula (5). Compounds of formula (8a) can be prepared fromthe bromide (5) upon treatment with aryl, heteroaryl or heterocyclicboronic acids or boronate esters (7a) under palladium catalystconditions such as, but not limited to,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) in thepresence of water and an inorganic base such as, but not limited to,sodium carbonate, potassium carbonate, or potassium phosphate in anorganic solvent such as, but not limited to, 1,4-dioxane at an elevatedtemperature. Alternatively, reaction between bromide (5) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in thepresence of base such as, but not limited to, potassium acetate orpotassium 2-ethyl heanoate, under palladium catalyst conditions such as,but not limited to, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of an organic solvent such as, butnot limited to, 1,4-dioxane or dimethylformamide, can produce thecorresponding boronate ester that upon treatment with aryl, heteroarylor heterocyclic halides under the analogous palladium catalystconditions can also yield compounds of formula (8a). To access compoundsof formula (11a), Boc-protected (4) can be directly elaborated tocompounds of formula (9a) using either coupling procedure describedabove. Subjection of piperidine (9a) to the protic conditions describedabove, followed by treatment with a base such as, but not limited to,triethylamine (TEA), and urea (10) provides compounds of formula (11a).

Compounds of formula (15) may be prepared by general synthetic methodsas shown in Scheme 4.

Compounds of formula (15) can be prepared from the bromide (13) upontreatment with aryl, heteroaryl or heterocyclic boronic acids orboronate esters under palladium catalyst conditions such as, but notlimited to, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)orchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) in the presence of water and an inorganic base such as,but not limited to, sodium carbonate in an organic solvent such as, butnot limited to, 1,4-dioxane at an elevated temperature. Alternatively,reaction between triflate (12) under the analogous palladium catalystconditions can also yield compounds of formula (15).

Compounds of formula (18) may be prepared by general synthetic methodsas shown in Scheme 5.

Compounds of formula (18) can be prepared from the triflate (16) upontreatment with amines (17) in the presence of an organic solvent suchas, but not limited to, dimethyl sulfoxide (DMSO) under microwaveirradiation. When the salt form of amines (17) were utilized, a basesuch as, but not limited to, triethylamine was added to the reactionconditions.

Compounds of formulas (21) and (23) may be prepared by general syntheticmethods as shown in Scheme 6.

Compounds of formula (23) can be prepared from the bromide (5) upontreatment with indole or azaindole boronic acids or boronate esters (22)under palladium catalyst conditions such as, but not limited to,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) in thepresence of water and an inorganic base such as, but not limited to,sodium carbonate, potassium carbonate, or potassium phosphate in anorganic solvent such as, but not limited to, 1,4-dioxane at an elevatedtemperature. Alternatively, reaction between bromide (5) and indole orazaindole boronic acids or boronate esters (19) under the analogouspalladium catalyst conditions, followed by deprotection ofN-tert-butoxycarbonyl (Boc) group using a protic acid such as, but notlimited to, trifluoroacetic acid or hydrochloric acid yields compoundsof formula (21).

Compounds of formula (26) may be prepared by general synthetic methodsas shown in Scheme 7.

Compounds of formula (26) can be prepared from (24) upon treatment witharyl, heteroaryl, or heterocyclic iodides or bromides (25) under coppercatalyst conditions such as, but not limited to, copper (I) iodide inthe presence of an inorganic base such as, but not limited to, potassiumcarbonate or potassium phosphate and a ligand such as, but not limitedto, N,N′-dimethylethylenediame or (1R,2R)-cyclohexane-1,2-diamine in anorganic solvent such as, but not limited to, 1,4-dioxane at an elevatedtemperature.

Compounds of formula (28) may be prepared by general synthetic methodsas shown in Scheme 8.

Compounds of formula (28) can be prepared from the bromide (5) upontreatment with indoles or azaindoles (27) under copper catalystconditions such as, but not limited to, copper (I) iodide in thepresence of an inorganic base such as, but not limited to, potassiumphosphate and a ligand such as, but not limited to,(1R,2R)-cyclohexane-1,2-diamine in an organic solvent such as, but notlimited to, toluene at an elevated temperature.

Compounds of formula (34) may be prepared by general synthetic methodsas shown in Scheme 9.

Compounds of formula (32) can be prepared from the bromide (5) upontreatment with boronic esters or boronate acids (31) under palladiumcatalyst conditions such as, but not limited to,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) in thepresence of water and an inorganic base such as, but not limited to,sodium carbonate, in an organic solvent such as, but not limited to,1,4-dioxane at an elevated temperature. Treatment of the ester (32) withhydroxide sources such as, but not limited to, lithium hydroxide in thepresence of water and organic solvents such as, but not limited to,methanol and/or tetrahydrofuran yields carboxylic acids of formula (33).Reaction of carboxylic acids (33) with a coupling reagent such as, butnot limited to,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate, a base such as, but not limited to,diisopropylethylamine, and an amine (34) provides amides of formula(35).

General Procedure for Intermediates a & B

Step 1: ethyl 3-((tert-butoxycarbonyl)(2-cyanoethyl)amino)propanoate

To a solution of ethyl 3-aminopropanoate hydrochloride (366.5 g, 2.39mol) in MeOH (1.2 L) at room temperature was added NaOH (95.6 g, 2.39mol) in portions. The mixture was heated to 70° C., acrylonitrile (158g, 2.98 mol) was added dropwise and the reaction mixture stirred for 6h. The solution was cooled to 0° C. before (Boc)₂O (521 g, 2.39 mol) wasadded. The reaction was stirred at room temperature for 6 h, filtered,and washed with MeOH (200 mL). The filtrate was concentrated in vacuo togive a yellow oil residue that was re-dissolved in EtOAc and water (500mL). The aqueous layer was extracted with EtOAc (800 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (638 g) as light yellowoil that required no further purification. ¹H NMR (400 MHz, CDCl₃) δ4.17 (q, J=7.2 Hz, 2H), 3.68-3.62 (m, 4H), 2.57-2.53 (m, 4H), 1.49 (s,9H), 1.29 (t, J=7.2 Hz, 3H).

Step 2: tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate

To toluene (2.7 L) at 25° C. was added NaH (80 g, 2.0 mol) portion-wiseand the suspension was heated to 80° C. Ethyl3-((tert-butoxycarbonyl)(2-cyanoethyl)amino)propanoate (270 g, crude) inanhydrous toluene (270 mL) was added dropwise. The mixture was heated to100° C. and stirred for 5 hours. The mixture was cooled to roomtemperature, quenched with sat. aq. ammonium chloride (800 mL) andwashed with hexanes (800 mL). The aqueous phase was acidified with HCl(2 N) to pH 6 and then extracted with EtOAc (1 L×2). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (310 g) as yellow oilthat required no further purification. ¹H NMR (400 MHz, CDCl₃) δ4.17-4.14 (m, 1H), 3.59-3.56 (m, 2H), 3.43-3.41 (m, 2H), 2.70-2.66 (m,2H), 1.51 (s, 9H).

Step 3: tert-butyl3-amino-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

A mixture of tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (310 g,1.38 mol) and hydrazine mono-hydrate (140 mL, 2.08 mol) in EtOH (1.5 L)was heated to 60° C. for 2 h. The mixture was concentrated in vacuo togive the crude product that was dissolved in EtOAc (1 L) and washed withwater (1 L×2). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to afford the title compound (230 g,70%) as a colorless solid. ¹H NMR (400 MHz, CD₃OD) δ 4.28 (s, 2H),3.66-3.63 (m, 2H), 2.62-2.59 (m, 2H), 1.49 (s, 9H).

Step 4: tert-butyl3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a stirred mixture of tert-butyl3-amino-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (120 g,503.6 mmol), CuBr₂ (112.5 g, 503.6 mmol) and MeCN (1.2 L) at 0° C. wasadded isopentyl nitrite (76.7 g, 654.7 mmol) and the reaction mixturestirred for 20 min. The temperature was raised to 60° C. and thereaction mixture was stirred for an additional 5 h. After cooling thereaction to room temperature, the reaction mixture was quenched withwater (1 L) and the mixture was extracted with EtOAc (1 L×2). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=4:1) to afford the title compound(Intermediate A, 52 g, 34%) as light yellow solid. LCMS M/Z (M+H) 302.

Step 5: tert-butyl3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a stirred solution of tert-butyl3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate A, 32 g, 105.9 mmol) in THF at 0° C. (350 mL) was addedNaH (5.08 g, 127.1 mmol) and the mixture was stirred for 30 min.Methyliodide (18.05 g, 127.1 mmol) was added dropwise and the mixturestirred for an additional 2 h. The mixture was quenched with water andextracted with EtOAc (300 mL×2). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (petroleumether/EtOAc=8:1) to afford the title compound (16 g, 48%) as a colorlessoil. ¹H NMR (400 MHz, CD₃OD) δ 4.24 (s, 2H), 3.70 (s, 3H), 3.69-3.67 (m,2H), 2.70-2.67 (m, 2H), 1.47 (s, 9H).

Step 6:1-(3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

A mixture of tert-butyl3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(12 g, 38.0 mmol) and trifluoroacetic acid (40 mL) in DCM (80 mL) wasstirred at room temperature for 2 h. The mixture was concentrated invacuo and the residue was re-dissolved in DCM (120 mL). The mixture wascooled to 0° C. before TEA (12.1 g, 120 mmol) and acetic anhydride (5.3g, 52 mmol) were added dropwise. The mixture stirred at room temperaturefor an additional 2 h before water (100 mL) was added. The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (DCM/MeOH=20:1)to afford the title compound (Intermediate B, 8.5 g, 87%) as whitesolid. H NMR (400 MHz, CD₃OD) δ 4.40-4.39 (m, 2H), 3.88-3.78 (m, 2H),3.72 (s, 3H), 2.83-2.70 (m, 2H), 2.20-2.17 (m, 3H).

General Procedure for Intermediate C

Step 1: tert-butyl3-bromo-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a stirred solution of tert-butyl3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate A, 6.0 g, 19.8 mmol) in DMF (40 mL) was added Cs₂CO₃ (9.70g, 29.8 mmol) and (bromomethyl)cyclopropane (4.0 g, 29.8 mmole). Thereaction mixture was heated to 80° C. for 12 h. The mixture was dilutedwith EtOAc (200 mL), washed with brine (100 mL×3), dried over Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified bysilica gel chromatography (eluent gradient from petroleum ether topetroleum ether/tert-butyl methyl ether/THF=10:1:1) to give the titlecompound (3.0 g, 42%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 4.29(s, 2H), 3.85 (d, J=3.4 Hz, 2H), 3.71 (t, J=5.2 Hz, 2H), 2.67 (t, J=5.2Hz, 2H), 1.49 (s, 9H), 1.25-1.18 (m, 1H), 0.61-0.55 (m, 2H), 0.35-0.31(m, 2H).

Step 2:1-(3-bromo-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

A mixture of tert-butyl3-bromo-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(3.0 g, 8.4 mmol) and trifluoroacetic acid (30 mL) in DCM (30 mL) wasstirred at room temperature for 2 h. The solvent was concentrated invacuo and the crude product was re-dissolved in DCM (120 mL). Thesolution was cooled to 0° C. before TEA (2.49 g, 24.6 mmol) and aceticanhydride (1.26 g, 12.3 mmol) were added dropwise. The reaction mixturewas stirred at room temperature for additional 2 h before it wasquenched with water. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified bysilica gel chromatography (DCM/MeOH=20:1) to afford the title compound(2.40 g, 96%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 4.49-4.33 (m,3H), 3.90-3.70 (m, 4H), 2.77-2.67 (m, 2H), 2.23-2.19 (m, 3H), 1.28-1.18(m, 1H), 0.63-0.58 (m, 2H), 0.36-0.32 (m, 2H).

General Procedure for Intermediate D

Step 1: tert-butyl3-bromo-1-(oxetan-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate A, 40.0 g, 132 mmol) in DMF (500 mL) was added Cs₂CO₃ (87g, 264 mmol) and 3-iodooxetane (27 g, 146 mmol). The mixture was heatedto 60° C. for 12 h before 3-iodooxetane (5 g, 27.0 mmol) was added andthe mixture was stirred at 60° C. for an additional 6 h. After coolingthe reaction to room temperature, the mixture was filtered, washed withEtOAc (500 mL) and concentrated in vacuo. The crude residue was purifiedby silica gel chromatography (petroleum ether:tert-butyl methylether:THF=from 100:1:1 to 5:1:1) to give the title compound (30 g, 64%)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 5.30-5.25 (m 1H), 5.18-5.14(m, 2H), 4.95-4.91 (m, 2H), 4.28 (s, 2H), 3.73-3.66 (m, 2H), 2.64 (t,J=5.6 Hz, 2H), 1.48 (s, 9H).

Step 2:1-(3-bromo-1-(oxetan-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of tert-butyl3-bromo-1-(oxetan-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(25.0 g, 70.0 mmol) in DCM (50 mL) was added trifluoroacetic acid (50mL) dropwise at 0° C. The mixture was stirred at room temperature for 2h. The mixture was concentrated in vacuo and the residue wasre-dissolved in DCM (500 mL). The mixture was cooled to 0° C. beforetriethylamine (48.8 mL, 350 mmol) and acetic anhydride (7.2 g, 70.0mmol) were added dropwise. The mixture was stirred at room temperaturefor additional 2 h. The reaction was quenched with water. The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel chromatography(DCM/MeOH=80:1) to give the title compound (Intermediate D, 17.0 g, 81%)as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 5.32-5.27 (m 1H),5.16-5.13 (m, 2H), 4.95-4.91 (m, 2H), 4.47-4.31 (m, 2H), 3.88-3.70 (m,2H), 2.75-2.63 (m, 2H), 2.17 (s, 3H).

General Procedure for Intermediate E

Step 1: (R)-tetrahydrofuran-3-yl methanesulfonate

To a solution of (R)-tetrahydrofuran-3-ol (25 g, 253.7 mmol) in DCM (250mL) at 0° C. was added triethylamine (119 mL, 851.2 mmol) and mesylchloride (39 g, 340.48 mmol) dropwise. The mixture was stirred at roomtemperature for 12 h. The reaction was quenched with water (100 mL) andextracted with DCM (100 mL×2). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give thetitle compound (47 g, 99%) as a brown oil. ¹H NMR (400 MHz, CDCl₃) δ5.35-5.27 (m, 1H), 4.05-3.83 (m, 4H), 3.04 (s, 3H), 2.28-2.20 (m, 2H).

Step 2: (S)-tert-butyl3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate A, 24.8 g, 82 mmol) in DMF (200 mL) was added Cs₂CO₃ (79g, 246 mmol) and (R)-tetrahydrofuran-3-yl methanesulfonate (17.4 g, 98mmol). The mixture was heated to 80° C. for 12 h. After cooling thereaction to room temperature, the mixture was concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (petroleumether/EtOAc=from 10:1 to 3:1) to give the title compound (50 g, 71%) asa yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 4.97-4.78 (m, 1H), 4.13 (s,2H), 3.98-3.86 (m, 2H), 3.81-3.67 (m, 2H), 3.56 (t, J=5.6 Hz, 2H), 2.68(t, J=5.6 Hz, 2H), 2.33-2.08 (m, 2H), 1.38 (s, 9H).

Step 3:(S)-1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of (S)-tert-butyl3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(29 g, 78 mmol) in DCM (300 mL) was added trifluroacetic acid (70 mL)dropwise. The mixture was stirred at room temperature for 2 h. Thesolvent was concentrated in vacuo and the crude residue was re-dissolvedin DMF (100 mL). The mixture was cooled to 0° C. before triethylamine(22 mL, 156 mmol) and acetic anhydride (8.7 g, 86 mmol) were addeddropwise. The mixture was stirred at room temperature for an additional2 h. The reaction was quenched with water (200 mL) at 0° C. andextracted with EtOAc (150 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (DCM/MeOH=30:1) togive the title compound (Intermediate E, 21.3 g, 87%) as a white solid.¹H NMR (400 MHz, CDCl₃) δ 4.78-4.67 (m, 1H), 4.45-4.29 (m, 2H),4.15-4.06 (m, 2H), 3.96-3.92 (m, 2H), 3.88-3.70 (m, 2H), 2.71-2.67 (m,2H), 2.38-2.34 (m, 2H), 2.16 (s, 3H).

General Procedure for Intermediate F

Step 1: tetrahydrofuran-3-yl methanesulfonate

To a solution of tetrahydrofuran-3-ol (10 g, 113.5 mmol) in DCM (150 mL)was added MsCl (15.6 g, 136.2 mmol) and TEA (23 g, 227 mmol). Thereaction mixture was stirred at room temperature for 18 h. Water (100mL) was added and the mixture was extracted with DCM (100 mL×2). Thecombined organic layers was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (16 g, 85%) as a brownoil. ¹H NMR (400 MHz, CDCl₃) δ 5.27-5.25 (m, 1H), 4.00-3.83 (m, 4H),3.01 (s, 3H), 2.23-2.18 (m, 2H).

Step 2: tert-butyl3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate A, 20.0 g, 66.0 mmol) in DMF (100 mL) was added Cs₂CO₃(40.0 g, 123 mmol) and tetrahydrofuran-3-yl methanesulfonate (16.0 g,98.0 mmol). The mixture was heated to 80° C. for 12 h. The solution wasconcentrated in vacuo and the crude residue was purified by silica gelchromatography (eluent from petroleum ether/EtOAc=10:1 to 3:1) to givethe title compound (17 g, 69%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃)δ 4.78-4.69 (m, 1H), 4.26 (s, 2H), 4.18-3.86 (m, 4H), 3.72 (s, 2H),2.72-2.62 (m, 2H), 2.44-2.22 (m, 2H), 1.48 (s, 9H).

Step 3:1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-]pyridin-5(4H)-yl)ethanone

To a solution of tert-butyl3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (17.0 g, 45.0 mmol) in DCM (60 mL) wasadded TFA (30 mL) dropwise. The reaction solution was stirred at roomtemperature for 2 h. The solvent was removed by evaporation and thecrude product was re-dissolved in DMF (50 mL). The mixture was cooled to0° C. before TEA (41.0 g, 40.5 mmol) and acetic anhydride (7.0 g, 68.0mmol) were added dropwise. The ice bath was removed and the reaction wasstirred at room temperature for additional 2 h. Water (50 mL) was addedand the solution was extracted with EtOAc (150 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=30:1) to give the title compound (IntermediateF, 12.0 g, 82%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 4.96-4.92(m 1H), 4.28 (s, 2H), 3.99-3.95 (m, 2H), 3.80-3.68 (m, 4H), 2.82-2.70(m, 2H), 2.29-2.19 (m, 2H), 2.10-2.08 (m, 3H).

General Procedure for Intermediates G & H

Step 1: tetrahydro-2H-pyran-4-yl methanesulfonate

To a solution of tetrahydro-2H-pyran-4-ol (5 g, 49.0 mmol) andtriethylamine (8.2 mL, 58.7 mmol) in DCM (100 mL) was added mesylchloride (16.8 g, 146.9 mmol) dropwise at 0° C. under a nitrogenatmosphere. The mixture was stirred at room temperature for 5 h. Water(100 mL) was added and extracted with DCM (100 mL×2). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (4 g, 45%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 4.85-4.81 (m 1H), 3.90-3.87 (m, 2H),3.52-3.46 (m, 2H), 2.99 (s, 3H), 2.01-1.97 (m, 2H), 1.83-1.80 (m, 2H).

Step 2: tert-butyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate A, 6 g, 19.8 mmol) in DMF (40 mL) was added Cs₂CO₃ (19.5g, 59.6 mmol) and tetrahydro-2H-pyran-4-yl methanesulfonate (3.9 g, 21.8mmol). The mixture was heated to 80° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered. The mixture was diluted with EtOAc (100 mL) and washedwith brine (100 mL×2). The organic layer was concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (petroleumether:tert-butyl methyl ether:THF=from 10:1:1 to 2:1:1) to give thetitle compound (Intermediate G, 3.2 g, 47%) as a clear oil. ¹H NMR (400MHz, DMSO-d₆) δ 4.35-4.25 (m, 1H), 4.17 (s, 2H), 3.95-3.93 (m, 2H),3.62-3.57 (m, 2H), 3.42 (t, J=11.2 Hz, 2H), 2.74-2.73 (m, 2H), 1.98-1.89(m, 2H), 1.80-1.77 (m, 2H), 1.41 (s, 9H).

Step 3:1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of tert-butyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate G, 3.2 g, 8.3 mmol) in DCM (20 mL) was addedtrifluoroacetic acid (20 mL) dropwise at 0° C. The mixture was stirredat room temperature for 2 h. The mixture was concentrated in vacuo andthe residue was re-dissolved in DCM (30 mL). The mixture was cooled to0° C. before triethylamine (2.9 mL, 21 mmol) and acetic anhydride (0.93g, 9.1 mmol) were added dropwise. The mixture was stirred at roomtemperature for an additional 0.5 h. The reaction was quenched withwater (60 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified bysilica gel chromatography (DCM/MeOH=50:1) to give the title compound(Intermediate H, 2.1 g, 77%) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 4.33-4.29 (m, 1H), 4.28 (s 2H), 3.95-3.92 (m, 2H), 3.70-3.67(m, 2H), 3.43-3.36 (m, 2H), 2.84-2.69 (m, 2H), 2.09-2.08 (m, 3H),1.96-1.91 (m, 2H), 1.80-1.76 (m, 2H).

General Procedure for Intermediate I

Step 1: N-(2-chlorobenzyl)-2,2-dimethoxyacetamide

To a solution of 2-chlorobenzylamine (30.0 g, 212 mmol) in MeOH (200 mL)was added triethylamine (36.7 mL, 265 mmol) and methyl dimethoxyacetate(31.0 g, 233 mmol). The reaction was heated to 80° C. for 20 h. Aftercooling to room temperature, the reaction was concentrated in vacuo.EtOAc (300 ml) was added, washed with 1N HCl (300 mL×2) and sat. aq.NaHCO₃ (300 mL×2). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the title compound (40.0 g,crude) as colorless oil that required no further purification. ¹H NMR(400 MHz, CDCl₃) δ 7.39-7.33 (m, 2H), 7.24-7.21 (m, 2H), 4.73 (s, 1H),4.56 (d, J=6.0 Hz, 2H), 3.38 (s, 6H).

Step 2: 8-chloroisoquinolin-3(2H)-one

To a solution of concentrated sulfuric acid (100 mL) at 0° C. was addedN-(2-chlorobenzyl)-2,2-dimethoxyacetamide (40.0 g, 164 mmol). Thereaction was stirred at room temperature for 16 h. The reaction waspoured into ice water and the mixture was basified with ammoniumhydroxide to pH 8. The yellow precipitate was filtered off, washed withwater, and dried in vacuo to give the title compound (20.0 g, crude) asa yellow solid that required no further purification. ¹H NMR (400 MHz,CDCl₃) δ 9.11 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.56-7.52 (m, 1H), 7.45(d, J=7.6 Hz, 1H), 7.00 (s, 1H).

Step 3: 8-chloro-3-((triisopropylsilyl)oxy)isoquinoline

To a solution of 8-chloroisoquinolin-3(2H)-one (12.0 g, 66.8 mmol) inDMF (15 mL) at 0° C. was added imidazole (13.6 g, 200.5 mmol) andchlorotriisopropylsilane (17.2 mL, 80.2 mmol). The reaction was stirredat room temperature for 12 h. The reaction mixture was concentrated invacuo. The crude residue was dissolved in EtOAc (70 mL) and washed withH₂O (40 mL×2). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified bysilica gel column chromatography (petroleum ether) to give the titlecompound (13.0 g, 62%) as colourless oil. ¹H NMR (400 MHz, DMSO-d₆) δ9.16 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.65-7.56 (m, 1H), 7.55-7.47 (m,1H), 7.23 (s, 1H), 1.46-1.30 (m, 3H), 1.06 (d, J=7.6 Hz, 18H).

Step 4:8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((triisopropylsilyl)-oxy)isoquinoline

To a solution of 8-chloro-3-((triisopropylsilyl)oxy)isoquinoline (13.0g, 38.7 mmol) in 1,4-dioxane (10 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (913 mg, 1.2mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (19.6g, 77.4 mmol) and KOAc (11.4 g, 116.1 mmol). The mixture was heated to80° C. for 2 h under a nitrogen atmosphere. After cooling the reactionto room temperature, the reaction mixture was used to the next stepdirectly without further purification. LCMS M/Z (M-TIPS+H) 272.

Step 5:1-(1-(tetrahydro-2H-pyran-4-yl)-3-(3-((triisopropylsilyl)oxy)isoquinolin-8-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To the above step cooled solution was added1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 8.9 g, 27.0 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.2 g, 1.5mmol) and K₃PO₄ (20.5 g, 96.5 mmol), 1,4-dioxane (5 mL) and water (3mL). The reaction mixture was heated to 90° C. for 4 h under a nitrogenatmosphere. After cooling to room temperature, the mixture was filteredand concentrated in vacuo. DCM (60 mL) was added and washed with water(50 mL×2). The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=20:1) to give the title compound (6.0 g, 28%)as a brown solid. LCMS M/Z (M-TIPS+H) 393.

Step 6:1-(3-(3-hydroxyisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(1-(tetrahydro-2H-pyran-4-yl)-3-(3-((triisopropylsilyl)oxy)isoquinolin-8-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(6.0 g, 10.9 mmol) in THF (10 mL) at 20° C. was added TBAF (54.7 ml,54.7 mmol, 1 M in THF). The reaction was stirred at room temperature for12 h. The reaction mixture was concentrated in vacuo. The crude residuewas dissolved in DCM (50 mL) and washed with H₂O (150 mL×2). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel chromatography(DCM/MeOH=10:1) to give the title compound (5.0 g, 86% purity) as abrown solid. LCMS M/Z (M+H) 393.

Step 7:8-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoquinolin-3-yltrifluoromethanesulfonate

To a solution of1-(3-(3-hydroxyisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(5.0 g, 12.7 mmol) in DCM (10 mL) at 0° C. was added triethylamine (5.3mL, 38.2 mmol) and trifluoromethanesulfonic anhydride (3.2 mL, 19.1mmol). The reaction was stirred at room temperature for 1 h. DCM (100mL) was added and washed with water (80 mL×2). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (EtOAc) to givethe title compound (Intermediate I, 1.7 g, 23%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.84-9.74 (m, 1H), 8.21 (s, 1H), 8.16 (d, J=8.4 Hz,1H), 8.05-7.95 (m, 1H), 7.84-7.72 (m, 1H), 4.59 (s, 2H), 4.50-4.45 (m,1H), 4.05-3.98 (m, 2H), 3.89-3.74 (m, 2H), 3.51 (d, J=12.0 Hz, 1H),3.01-2.80 (m, 2H), 2.20-2.00 (m, 5H), 1.99-1.88 (m, 2H).

Example 1 (Procedure A)1-(3-(1H-indol-3-yl)-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: tert-butyl3-(5-acetyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indole-1-carboxylate

To a solution of1-(3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate B, 500 mg, 1.92 mmol) in 1,4-dioxane (8 mL) and water (2mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (146 mg, 0.2mmol), Na₂CO₃ (408 mg, 3.84 mmol) and(1-(tert-butoxycarbonyl)-1H-indol-3-yl)boronic acid (552 mg, 2.1 mmol).The mixture was heated to 110° C. for 18 h under a nitrogen atmosphere.After cooling the reaction to room temperature, the mixture was filteredand concentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=20:1) to give the title compound (400 mg, 53%)as a brown solid.

Step 2:1-(3-(1H-indol-3-yl)-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of tert-butyl3-(5-acetyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indole-1-carboxylate(200 mg, 0.51 mmol) in DCM (2 mL) at 0° C. was added trifluoroaceticacid (2 mL, 3.4 mmol). The mixture was stirred at room temperature for 2h and concentrated in vacuo. The crude residue was purified by reversephase chromatography (acetonitrile 30-60%/0.1% NH₄OH in water) to givethe title compound (15 mg, 10%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.23 (s, 1H), 8.26-8.21 (m, 1H), 7.52-7.40 (m, 2H),7.15-7.06 (m, 2H), 4.58 (s, 2H), 3.85-3.68 (m, 5H), 2.80-2.68 (m, 2H),2.12 (s, 3H). LCMS M/Z (M+H) 295.

Example 2 (Procedure B)1-(1-methyl-3-(1-methyl-1H-indol-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-(1H-indol-3-yl)-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Example 1, 150 mg, 0.51 mmol) in DMF (2 mL) at 0° C. was added sodiumhydride (60%, 41 mg, 1.02 mmol) by portionwise. The mixture was stirredat room temperature for 0.5 h. Iodomethane (0.073 mL, 1.02 mmol) wasadded dropwise and the mixture stirred at room temperature for anadditional 1 h. The mixture was quenched with water (20 mL) andextracted with EtOAc (20 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by reverse phase chromatography (acetonitrile36-66%/0.1% NH₄OH in water) to give the title compound (47 mg, 29%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28-8.24 (m, 1H), 7.55-7.42(m, 2H), 7.22-7.18 (m, 1H), 7.12-7.08 (m, 1H), 4.61-4.54 (m, 2H), 3.85(s, 1H), 3.79-3.72 (m, 5H), 2.82-2.67 (m, 2H), 2.13-2.07 (m, 3H). LCMSM/Z (M+H) 309.

Example 3 (Procedure C)1-(1-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)-6,7-dihydro-H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: tert-butyl 6-bromo-1H-indole-1-carboxylate

To a solution of 6-bromo-1H-indole (10.0 g, 51.0 mmol) in DCM (100 mL)was added di-tert-butyl dicarbonate (13.4 g, 61.2 mmol), DMAP (623 mg,5.1 mmol) and triethylamine (21.2 mL, 153.0 mmol). The mixture wasstirred at 20° C. for 16 h under a nitrogen atmosphere. The mixture wasconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=10:1) to give the title compound(14.5 g, 96%) as a yellow solid.

Step 2: tert-butyl 6-(1-methyl-1H-pyrazol-4-yl)-1H-indole-1-carboxylate

To a solution of tert-butyl 6-bromo-1H-indole-1-carboxylate (10.0 g,33.8 mmol) in 1,4-dioxane (90 mL) and water (30 mL) was added[1,1′-is(diphenylphosphino)ferrocene]-dichloropalladium (II) (2.0 g, 3.4mmol), Na₂CO₃ (10.7 g, 101.3 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(8.4 g, 40.5 mmol). The mixture was heated to 110° C. for 16 h under anitrogen atmosphere. After cooling the reaction to room temperature,water (100 mL) was added and extracted with EtOAc (100 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=2:1) to give the title compound(9.0 g, 90%) as a light brown solid.

Step 3: tert-butyl3-bromo-6-(1-methyl-1H-pyrazol-4-yl)-1H-indole-1-carboxylate

To a solution of tert-butyl6-(1-methyl-1H-pyrazol-4-yl)-1H-indole-1-carboxylate (7.5 g, 25.2 mmol)in DCM (80 mL) was added N-bromosuccinimide (4.49 g, 25.2 mmol). Themixture was stirred at 40° C. for 16 h under a nitrogen atmosphere.Water (120 mL) was added and the mixture was extracted with DCM (120mL×2). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the title compound (7.0 g,74%) as brown oil that required no further purification.

Step 4: tert-butyl6-(1-methyl-1H-pyrazol-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

To a solution of tert-butyl3-bromo-6-(1-methyl-1H-pyrazol-4-yl)-1H-indole-1-carboxylate (7.0 g,18.6 mmol) in DMF (40 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.4 g, 1.9mmol), KOAc (5.5 g, 55.8 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (7.0 g, 27.9mmol). The mixture was heated to 70° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas concentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=5:1) to give the title compound(3.0 g, 38%) as a yellow oil.

Step 5: tert-butyl3-(5-acetyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-indole-1-carboxylate

To a solution of1-(3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate B, 838 mg, 3.25 mmol) in 1,4-dioxane (15 mL) and water (5mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (238 mg,0.33 mmol), K₂CO₃ (898 mg, 6.50 mmol) and tert-butyl6-(1-methyl-1H-pyrazol-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate(2.5 g, 3.25 mmol). The mixture was heated to 70° C. for 16 h under anitrogen atmosphere. After cooling the reaction to room temperature,water (50 mL) was added and extracted with EtOAc (60 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=20:1) to give the title compound (1.0 g, 65%)as a brown solid.

Step 6:1-(1-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of tert-butyl3-(5-acetyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-indole-1-carboxylate(700 mg, 1.48 mmol) in DCM (7 mL) was added trifluoroacetic acid (7 mL).The mixture was stirred at 20° C. for 3 h under a nitrogen atmosphere.The mixture was concentrated in vacuo to give the crude residue that wasdissolved in EtOAc (50 mL), washed with sat. aq. NaHCO₃ (50 mL×2) andbrine (50 mL×2), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The crude residue was purified by recrystallization to givethe title compound (202 mg, 36%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.21 (s, 1H), 8.21-8.15 (m, 1H), 8.08 (s, 1H), 7.83 (s, 1H),7.52 (s, 1H), 7.47-7.37 (m, 1H), 7.28-7.26 (m, 1H), 4.57 (s, 2H), 3.86(s, 3H), 3.80-3.68 (m, 5H), 2.80-2.67 (m, 2H), 2.11 (s, 3H). LCMS M/Z(M+H) 375.

Example 4 (Procedure D)1-(3-(6-methylisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: N-(2-bromo-4-chlorobenzylidene)-2,2-dimethoxyethanamine

To a solution of 2-bromo-4-chlorobenzaldehyde (40.0 g, 182.27 mmol) intoluene (100 mL) was added 2,2-dimethoxyethanamine (19.16 g, 182.27mmol). The mixture was heated to 110° C. for 16 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas concentrated in vacuo to give the title compound (59.0 g, crude) ascolorless oil that required no further purification. ¹H NMR (400 MHz,CDCl₃) δ 8.57 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.31-7.28(m, 1H), 4.67 (t, J=5.2 Hz, 1H), 3.80 (d, J=4.4 Hz, 2H), 3.41 (s, 6H).

Step 2: N-(2-bromo-4-chlorobenzyl)-2,2-dimethoxyethanamine

To a solution of N-(2-bromo-4-chlorobenzylidene)-2,2-dimethoxyethanamine(59.0 g, 192.45 mmol) in MeOH (200 mL) at 0° C. was added sodiumborohydride (5.82 g, 153.96 mmol) portionwise. The mixture was stirredat 28° C. for 2 h under a nitrogen atmosphere and concentrated in vacuo.Water (200 mL) was added and extracted with DCM (200 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (60.0 g, crude) ascolorless oil that required no further purification. LCMS M/Z (M+H) 308.

Step 3:N-(2-bromo-4-chlorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide

To a solution of N-(2-bromo-4-chlorobenzyl)-2,2-dimethoxyethanamine(60.0 g, 194.43 mmol) in DCM (300 mL) at 0° C. was added4-methylbenzene-1-sulfonyl chloride (37.0 g, 194.43 mmol),N,N-dimethylpyridin-4-amine (1.19 g, 9.72 mmol) and triethylamine (53.9mL, 388.85 mmol). The mixture was stirred at 28° C. for 10 h under anitrogen atmosphere. Water (300 mL) was added and extracted with DCM(300 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=5:1) togive the title compound (70 g, 78%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.72 (d, J=7.6 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J=8.4 Hz, 1H),7.35-7.27 (m, 3H), 4.48 (s, 2H), 4.36 (t, J=5.2 Hz, 1H), 3.29 (d, J=5.2Hz, 2H), 3.23 (s, 6H), 2.45 (s, 3H). LCMS M/Z (M+H) 462.

Step 4: 8-bromo-6-chloroisoquinoline

To a solution of aluminum trichloride (43.22 g, 324.12 mmol) in1,2-dichloroethane (200 mL) at 0° C. was addedN-(2-bromo-4-chlorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide(30.0 g, 64.82 mmol) in 1,2-dichloroethane (200 mL) dropwise. Themixture was stirred at 28° C. for 16 h under a nitrogen atmosphere andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=10:1) to give the title compound(6.2 g, 39%) as a yellow solid. LCMS M/Z (M+H) 242.

Step 5:6-chloro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline

To a solution of 8-bromo-6-chloroisoquinoline (3.0 g, 12.37 mmol) in1,4-dioxane (50 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (905 mg,1.24 mmol), potassium 2-ethylhexanoate (3.38 g, 18.56 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.71 g,18.56 mmol). The mixture was heated to 80° C. for 1 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 290.

Step 6:1-(3-(6-chloroisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To the above step cooled solution was added1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 6.12 g, 18.65 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (758 mg,1.04 mmol) and K₃PO₄ (4.40 g, 20.72 mmol), 1,4-dioxane (30 mL) and water(20 mL). The reaction mixture was heated to 80° C. for 8 h undernitrogen atmosphere. After cooling to room temperature, the mixture wasfiltered and concentrated in vacuo. EtOAc (200 mL) was added and washedwith water (120 mL×2). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (DCM/MeOH=30:1) to give the titlecompound (1.6 g, 31%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ9.78-9.70 (m, 1H), 8.58 (d, J=5.6 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J=5.6Hz, 1H), 7.68-7.55 (m, 1H), 4.55 (s, 2H), 4.54-4.42 (m, 1H), 4.06-3.96(m, 2H), 3.87-3.77 (m, 2H), 3.51 (t, J=12.0 Hz, 2H), 3.01-2.80 (m, 2H),2.15-2.00 (m, 5H), 1.98-1.87 (m, 2H). LCMS M/Z (M+H) 411.

Step 7:1-(3-(6-methylisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-(6-chloroisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(200 mg, 0.49 mmol) in toluene (10 mL) and water (2 mL) was addedpotassium methyltrifluoroborate (59 mg, 0.49 mmol), butyldi-1-adamantylphosphine (175 mg, 0.49 mmol), palladium(II) acetate (109mg, 0.49 mmol) and Cs₂CO₃ (159 mg, 0.49 mmol). The mixture was heated to80° C. for 16 h under a nitrogen atmosphere. After cooling the reactionto room temperature, EtOAc (100 mL) was added and washed with water (100mL×3) and brine (100 mL). The organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by reverse phase chromatography (acetonitrile 30-60%/0.05%NH₄OH in water) to give the title compound (15 mg, 8%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.66 (s, 1H), 8.48 (d, J=6.0 Hz, 1H),7.81-7.73 (m, 2H), 7.54-7.42 (m, 1H), 4.52 (s, 2H), 4.51-4.40 (s, 1H),4.08-3.95 (m, 2H), 3.87-3.76 (m, 2H), 3.52 (t, J=12.0 Hz, 2H), 3.00-2.81(m, 2H), 2.56 (s, 3H), 2.13-2.03 (m, 5H), 2.01-1.94 (m, 2H). LCMS M/Z(M+H) 391.

Example 5 (Procedure E)1-(3-(6-methoxyisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-(6-chloroisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(200 mg, 0.49 mmol) in 1,4-dioxane (6 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (46 mg, 0.10mmol),methanesulfonato(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(82 mg, 0.10 mmol), t-BuONa (65 mg, 0.68 mmol) and MeOH (0.1 mL, 2.43mmol). The mixture was heated to 50° C. for 20 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. The crude residue was purifiedby reverse phase chromatography (acetonitrile 15-45%/0.05% NH₄OH inwater) to give the title compound (30 mg, 90% purity) which was furtherseparated by using chiral SFC (SFC 80; Chiralpak AS 250×30 mm I.D, 5 um;Supercritical CO₂/MeOH+NH₃.H₂O=30/30; 60 ml/min) to give the titlecompound (18 mg, 9%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ9.66-9.59 (m, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.75 (d, J=5.6 Hz, 1H), 7.36(d, J=2.4 Hz, 1H), 7.24-7.14 (m, 1H), 4.51 (s, 2H), 4.50-4.39 (m, 1H),4.05-3.95 (m, 2H), 3.94 (s, 3H), 3.86-3.76 (m, 2H), 3.51 (t, J=12.0 Hz,2H), 3.00-2.79 (m, 2H), 2.16-2.00 (m, 5H), 1.99-1.87 (m, 2H). LCMS M/Z(M+H) 407.

Example 6 (Procedure F)1-(1-(tetrahydro-2H-pyran-4-yl)-3-(6-vinylisoquinolin-8-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-(6-chloroisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(3.0 g, 7.3 mmol) in THF (30 mL) and water (6 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (348 mg, 0.73mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (574 mg, 0.73 mmol), Na₂CO₃ (1.55 g, 14.6 mmol) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.46 g, 9.49 mmol). Themixture was heated to 60° C. for 16 h under a nitrogen atmosphere. Aftercooling the reaction to room temperature, the mixture was filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=30:1) to give the title compound (1.5 g, 51%)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.70-9.64 (m, 1H), 8.50(d, J=5.6 Hz, 1H), 7.96 (s, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.74 (s, 1H),7.04-6.92 (m, 1H), 6.12 (d, J=17.6 Hz, 1H), 5.51 (d, J=11.2 Hz, 1H),4.53 (s, 2H), 4.48-4.38 (m, 1H), 4.04-3.95 (m, 2H), 3.87-3.76 (m, 2H),3.50 (t, J=11.6 Hz, 2H), 3.00-2.79 (m, 2H), 2.13-1.98 (m, 5H), 1.97-1.92(m, 2H). LCMS M/Z (M+H) 403.

Example 7 (Procedure G)1-(3-(6-ethylisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(1-(tetrahydro-2H-pyran-4-yl)-3-(6-vinylisoquinolin-8-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Example 6, 200 mg, 0.50 mmol) in MeOH (5 mL) was added 10% Pd/C (53mg). The mixture was stirred at room temperature for 24 h under ahydrogen atmosphere (15 Psi). The mixture was filtered and the filtratewas concentrated in vacuo. The crude residue was purified by reversephase chromatography (acetonitrile 15-45%/0.05% NH₄OH in water) to givethe title compound (14 mg, 7%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.67 (s, 1H), 8.48 (d, J=6.0 Hz, 1H), 7.80 (d, J=5.6 Hz, 1H),7.77 (s, 1H), 7.59-7.45 (m, 1H), 4.52 (s, 2H), 4.50-4.39 (m, 1H),4.05-3.93 (m, 2H), 3.88-3.74 (m, 2H), 3.51 (t, J=11.6 Hz, 2H), 2.99-2.77(m, 2H), 2.86 (q, J=7.6 Hz, 2H), 2.19-2.00 (m, 5H), 1.99-1.88 (m, 2H),1.31 (t, J=7.6 Hz, 2H). LCMS M/Z (M+1) 405.

Example 8 (Procedure H)1-(3-(6-(hydroxymethyl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1:8-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoquinoline-6-carbaldehyde

To a solution of1-(1-(tetrahydro-2H-pyran-4-yl)-3-(6-vinylisoquinolin-8-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Example 6, 300 mg, 0.75 mmol) in THF (3 mL) and water (3 mL) was addedosmium(VIII) oxide (500 mg, 1.97 mmol). The mixture was stirred at roomtemperature for 0.5 h. Sodium periodate (294 mg, 1.37 mmol) was addedand the mixture stirred for an additional 2 h. Water (30 mL) was addedand the mixture was extracted with EtOAc (30 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give the title compound (300 mg, crude) as a yellow solid thatrequired no further purification. LCMS M/Z (M+H) 405.

Step 2:1-(3-(6-(hydroxymethyl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of8-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoquinoline-6-carbaldehyde(300 mg, 0.74 mmol) in MeOH (5 mL) at 0° C. was added sodium borohydride(84 mg, 2.23 mmol). The mixture was stirred at room temperature for 1 hunder a nitrogen atmosphere. The reaction was concentrated in vacuo.Water (30 mL) was added and extracted with EtOAc (30 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (acetonitrile 13-43%/0.05% NH₄OH in water) to give thetitle compound (13 mg, 4%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ9.70 (s, 1H), 8.51 (d, J=5.6 Hz, 1H), 7.91-7.82 (m, 2H), 7.60-7.53 (m,1H), 5.53 (t, J=5.6 Hz, 2H), 7.75 (d, J=5.2 Hz, 1H), 4.61-4.41 (m, 1H),4.51 (s, 2H), 4.06-3.95 (m, 2H), 3.88-3.76 (m, 2H), 3.52 (t, J=12.0 Hz,2H), 3.03-2.79 (m, 2H), 2.19-2.00 (m, 5H), 1.99-1.95 (m, 2H). LCMS M/Z(M+1) 407.

Example 9 (Procedure I)1-(3-(5-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: (2-chloro-5-methylphenyl)methanamine

To a solution of 2-chloro-5-methyl-benzonitrile (9.0 g, 59.4 mmol) inanhydrous THF (90 mL) at 0° C. was added BH₃-THF (1.0 M, 178 mL, 178mmol) dropwise under a nitrogen atmosphere. The mixture was stirred atroom temperature for 12 h. The reaction was quenched with 2N HCl (110mL) at 0° C. and then heated to 70° C. for 1 h. After cooling thereaction to room temperature, the solution was washed with DCM (150 mL).The aqueous phase was basified with 1N NaOH to pH 8 and then extractedwith DCM (150 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (5.8 g, 63%) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.22 (d,J=8.0 Hz, 1H), 7.17 (s, 1H), 6.99 (d, J=8.0 Hz, 1H), 3.88 (s, 2H), 2.32(s, 3H).

Step 2: N-(2-chloro-5-methylbenzyl)-2,2-dimethoxyacetamide

To a solution of (2-chloro-5-methylphenyl)methanamine (4.6 g, 29.6 mmol)in MeOH (40 mL) was added triethylamine (5.2 mL, 37.2 mmol) and methyldimethoxyacetate (4.4 g, 33.1 mmol). The mixture was heated to 80° C.for 16 h in sealed tube. After cooling the reaction to room temperature,the mixture was concentrated in vacuo. EtOAc (100 mL) was added andwashed with 1N HCl (50 mL), WATER (50 mL), brine (50 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give the title compound (4.1 g, 54%) as colorless oil. ¹H NMR(400 MHz, DMSO-d₆) δ 8.47-8.37 (m, 1H), 7.28 (d, J=8.4 Hz, 1H),7.09-7.05 (s, 2H), 4.74 (s, 1H), 4.31 (d, J=6.4 Hz, 2H), 3.32 (s, 6H),2.25 (s, 3H).

Step 3: 8-chloro-5-methylisoquinolin-3(2H)-one

To a solution of sulfuric acid (40 mL) at 0° C. was addedN-(2-chloro-5-methylbenzyl)-2,2-dimethoxyacetamide (5.0 g, 19.4 mmol).The reaction was stirred at room temperature for 16 h. The reaction waspoured into ice water (100 mL) and the mixture was basified withammonium hydroxide to pH 8. The yellow precipitate was filtered off,washed with MeOH (10 mL), Et₂O (10 mL), and dried in vacuo to give thetitle compound (3.8 g, crude) as a yellow solid that required no furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (s, 1H), 7.37-7.30 (m,2H), 6.93 (s, 1H), 2.48 (s, 3H).

Step 4: 8-chloro-5-methylisoquinolin-3-yl trifluoromethanesulfonate

To a solution of 8-chloro-5-methylisoquinolin-3(2H)-one (1 g, 5.16 mmol)in DCM (10 mL) at 0° C. was added triethylamine (4.3 mL, 31 mmol) andtrifluoromethanesulfonic anhydride (1.3 mL, 7.75 mmol). The reaction wasstirred at room temperature for 1 h. DCM (50 mL) was added and washedwith ice water (40 mL×2). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound (2g, crude) as dark brown oil that required no further purification.

Step 5: 8-chloro-5-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline

To a solution of 8-chloro-5-methylisoquinolin-3-yltrifluoromethanesulfonate (2 g, crude) in 1,4-dioxane (10 mL) and water(2 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (449 mg, 0.6mmol), Na₂CO₃ (1.95 g, 18.4 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.4 g, 6.7 mmol). The mixture was irradiated in a microwave at 90° C.for 0.5 h. EtOAc (100 mL) was added and washed with water (60 mL×2),brine (60 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified bysilica gel chromatography (petroleum ether/EtOAc=1:1) to give the titlecompound (770 mg) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (s,1H), 8.45 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.59-7.53 (m. 2H), 3.92(s, 3H), 2.66 (s, 3H).

Step 6:1-(1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 200 mg, 0.6 mmol) in 1,4-dioxane (4 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (17 mg, 0.04mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (14 mg, 0.02 mmol), KOAc (179 mg, 1.8 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (309 mg, 1.2mmol). The mixture was heated to 80° C. for 2 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 376.

Step 7:1-(3-(5-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To the above step cooled solution was added8-chloro-5-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline (94 mg, 0.36mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (19 mg, 0.02 mmol), K₃PO₄ (322 mg, 1.5 mmol), 1,4-dioxane(1 mL) and water (1 mL). The reaction mixture was heated to 90° C. for 1h under a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. DCM (50 mL) was addedand washed with water (40 mL×2). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 20-50%/0.2%formic acid in water) to give the title compound (50 mg, 17%) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.66-9.62 (m, 1H), 8.08-8.06 (m,2H), 7.92-7.90 (m, 1H), 7.55-7.50 (m, 1H), 7.44-7.32 (m, 1H), 4.62-4.45(m, 2H), 4.34-4.21 (m, 1H), 4.19-4.14 (m, 2H), 4.09-3.77 (m, 2H), 4.00(s, 3H), 3.59-3.53 (m, 2H), 2.96-2.81 (m, 2H), 2.76-2.70 (m, 3H),2.48-2.37 (m, 2H), 2.24-2.02 (m, 3H), 2.00-1.88 (m, 2H). LCMS M/Z (M+H)471.

Example 10 (Procedure J)N-methyl-3-(5-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

Step 1: tert-butyl1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate G, 400 mg, 1.04 mmol) in 1,4-dioxane (10 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (30 mg, 0.06mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (25 mg, 0.03 mmol), KOAc (300 mg, 3.12 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (526 mg,2.08 mmol). The mixture was heated to 80° C. for 2 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 434.

Step 2: tert-butyl3-(5-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To the above step cooled solution was added8-chloro-5-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline (160 mg, 0.62mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (25 mg, 0.03 mmol), K₃PO₄ (661 mg, 3.12 mmol), 1,4-dioxane(5 mL) and water (3 mL). The reaction mixture was heated to 90° C. for12 h under a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. DCM (20 mL) was addedand washed with water (15 mL×2), brine (20 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (DCM/MeOH=20:1)to give the title compound (180 mg, 37%) as a yellow solid. LCMS M/Z(M+H) 529.

Step 3:5-methyl-3-(1-methyl-1H-pyrazol-4-yl)-8-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoquinoline

To a solution of tert-butyl3-(5-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(180 mg, 0.34 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.27mL, 3.6 mmol). The mixture was stirred at room temperature for 1 h andconcentrated in vacuo to give the title compound (100 mg, crude) asyellow oil that required no further purification. LCMS M/Z (M+H) 429.

Step 4:N-methyl-3-(5-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

To a solution of5-methyl-3-(1-methyl-1H-pyrazol-4-yl)-8-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoquinoline(100 mg, 0.23 mmol) in DCM (2 mL) was added triethylamine (0.1 mL, 0.70mmol) and N-methyl-1H-imidazole-1-carboxamide (58 mg, 0.47 mmol). Thereaction was stirred at room temperature for 12 h and concentrated invacuo. The crude residue was purified by reverse phase chromatography(acetonitrile 23-53%/0.05% NH₄OH in water) to give the title compound(12 mg, 10%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.58 (s,1H), 8.08-8.05 (m, 2H), 7.91 (s, 1H), 7.56-7.49 (m, 1H), 7.41-7.36 (m,1H), 4.47-4.39 (m, 1H), 4.35-4.21 (m, 3H), 4.20-4.12 (m, 2H), 4.00 (s,3H), 3.90-3.84 (m, 2H), 3.62-3.51 (m, 2H), 2.89-2.83 (m, 2H), 2.78 (d,J=4.4 Hz, 3H), 2.73 (s, 3H), 2.50-2.36 (m, 2H), 2.00-1.91 (m, 2H). LCMSM/Z (M+H) 486.

Example 11 (Procedure K)4-(8-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoquinolin-3-yl)-1-methyl-1H-pyrazole-3-carbonitrile

Step 1:1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-carbonitrile

To a solution of 4-bromo-1-methyl-1H-pyrazole-3-carbonitrile (150 mg,0.81 mmol) in 1,4-dioxane (4 mL) was added(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (38 mg, 0.08 mmol)andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (63 mg, 0.08 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (225 mg,0.88 mmol) and KOAc (237 mg, 2.42 mmol). The mixture was heated to 90°C. for 12 h under a nitrogen atmosphere. After cooling the reaction toroom temperature, the reaction mixture was used to the next stepdirectly without further purification. LCMS M/Z (M+H) 234.

Step 2:4-(8-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoquinolin-3-yl)-1-methyl-1H-pyrazole-3-carbonitrile

To the above step cooled solution was added8-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoquinolin-3-yltrifluoromethanesulfonate (Intermediate I, 100 mg, 0.19 mmol),(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (9 mg, 0.02 mmol)andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (15 mg, 0.02 mmol) and Na₂CO₃ (40 mg, 0.38 mmol),1,4-dioxane (1 mL) and water (1 mL). The reaction mixture was heated to60° C. for 16 h under a nitrogen atmosphere. After cooling to roomtemperature, the mixture was filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile25-55%/0.2% formic acid in water) to give the title compound (25 mg, 6%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (s, 1H), 8.68 (s,1H), 8.22 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.91-7.83 (m, 1H), 7.71-7.60(m, 1H), 4.55 (s, 2H), 4.52-4.42 (m, 1H), 4.07-3.97 (m, 2H), 4.03 (s,1H), 3.88-3.78 (m, 2H), 3.52 (d, J=12.0 Hz, 2H), 3.02-2.82 (m, 2H),2.17-2.01 (m, 5H), 2.00-1.89 (m, 2H). LCMS M/Z (M+H) 482.

Example 12 (Procedure L)5-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

Step 1:1-(1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 600 mg, 1.83 mmol) in 1,4-dioxane (4 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (52 mg, 0.11mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (43 mg, 0.05 mmol), KOAc (538 mg, 5.48 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (928 mg,3.66 mmol). The mixture was heated to 80° C. for 3 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 376.

Step 2:5-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one

To the above step cooled solution was added5-bromo-3,4-dihydroisoquinolin-1(2H)-one (238 mg, 1.06 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (47 mg, 0.06 mmol), K₃PO₄ (509 mg, 2.4 mmol), 1,4-dioxane(1 mL) and water (1 mL). The reaction mixture was heated to 90° C. for 1h under a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. Water (100 mL) was addedand extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine (50 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=30:1) to give the title compound (250 mg, 35%)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.15-8.11 (m, 1H), 7.46-7.39(m, 2H), 6.29-6.22 (m, 1H), 4.58-4.42 (m, 2H), 4.26-4.10 (m, 3H),3.97-3.80 (m, 2H), 3.61-3.45 (m, 4H), 3.20-3.09 (m, 2H), 2.86-2.80 (m,2H), 2.38-2.27 (m, 2H), 2.20-2.11 (m, 3H), 1.94-1.85 (m, 2H). LCMS M/Z(M+H) 395.

Step 3:5-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

To a solution of5-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one(100 mg, 0.25 mmol) in 1,4-dioxane (10 mL) was added copper(I) iodide (2mg, 0.01 mmol), (1R,2R)-cyclohexane-1,2-diamine (6 mg, 0.05 mmol), K₃PO₄(161 mg, 0.76 mmol) and 4-iodo-1-methyl-1H-pyrazole (79 mg, 0.38 mmol).The reaction mixture was heated to 100° C. for 12 h under a nitrogenatmosphere. After cooling to room temperature, the mixture was filteredand concentrated in vacuo. Water (50 mL) was added and extracted withDCM (30 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by reverse phase chromatography (acetonitrile 26-56%/0.2%formic acid in water) to give the title compound (37 mg, 31%) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.20-8.10 (m, 2H), 7.54 (d,J=5.2 Hz, 1H), 7.49-7.36 (m, 2H), 4.61-4.45 (m, 2H), 4.27-4.11 (m, 3H),4.02-3.78 (m, 4H), 3.93 (s, 3H), 3.61-3.50 (m, 2H), 3.36-3.28 (m, 2H),2.90-2.77 (m, 2H), 2.40-2.27 (m, 2H), 2.20-2.11 (m, 3H), 1.95-1.86 (m,2H). LCMS M/Z (M+H) 475.

Example 13 (Procedure M)1-(3-(2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: 2-methyl-5-(1-methyl-H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridine

To a solution of 5-chloro-2-methyl-1H-pyrrolo[2,3-c]pyridine (900 mg,5.4 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (258 mg, 0.54mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (425 mg, 0.54 mmol), Na₂CO₃ (1.72 g, 16.2 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.35 g, 6.48 mmol). The mixture was heated to 100° C. for 16 h under anitrogen atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (DCM/MeOH=10:1) to give the titlecompound (700 mg, 61%) as a white solid. LCMS M/Z (M+H) 213.

Step 2:1-(3-(2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 250 mg, 0.76 mmol) in toluene (10 mL) was addedcopper(I) iodide (7 mg, 0.04 mmol), K₃PO₄ (646 mg, 3.05 mmol),(1R,2R)-cyclohexane-1,2-diamine (17 mg, 0.15 mmol) and2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridine (162 mg,0.76 mmol). The mixture was heated to 120° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. Water (100 mL) was added andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (acetonitrile 20-50%/0.05% NH₄OH in water) to give thetitle compound (6 mg, 2%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.38-8.34 (m, 1H), 7.95 (s, 1H), 7.89-7.86 (m, 1H), 7.64-7.60 (m, 1H),6.40-6.36 (m, 1H), 4.40-4.19 (m, 3H), 4.17-4.12 (m, 2H), 4.06-3.81 (m,2H), 3.96 (s, 3H), 3.56 (t, J=12.0 Hz, 2H), 2.95-2.81 (m, 2H), 2.42-2.27(m, 5H), 2.19-2.04 (m, 3H), 1.95-1.92 (m, 2H). LCMS M/Z (M+H) 460.

Examples 14 & 15 (Procedure N)(S)-1-[8-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-isoquinolyl]-N-methyl-pyrrolidine-3-carboxamideand(R)-1-[8-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-isoquinolyl]-N-methyl-pyrrolidine-3-carboxamide

To a microwave vial was added[8-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-isoquinolyl]trifluoromethanesulfonate (Intermediate I, 40.0 mg, 0.0763 mmol),N-methylpyrrolidine-3-carboxamide (39.1 mg, 0.305 mmol), and then DMSO(1.0 mL). The mixture was heated to 130° C. for 0.5 h under microwaveconditions. After cooling to room temperature, the crude mixture waspurified by reverse phase preparative HPLC (acetonitrile 5-50%/0.1%ammonium hydroxide in water) to give racemic1-[8-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-isoquinolyl]-N-methyl-pyrrolidine-3-carboxamide(18.6 mg, 49%) as a yellow solid that was separated by chiral SFC(Chiralpak AD 150×21.2 mm I.D., 5 μm); Supercritical CO₂/MeOH (0.1%NH₃H₂O)=60:40 at 70 mL/min) to give(S)-1-[8-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-isoquinolyl]-N-methyl-pyrrolidine-3-carboxamide(6.7 mg, first peak) and(R)-1-[8-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-isoquinolyl]-N-methyl-pyrrolidine-3-carboxamide(7.4 mg, seconds peak). Absolute configuration was arbitrarily assignedto each diastereomer. Example 14: ¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (t,J=0.9 Hz, 1H), 7.95 (d, J=4.8 Hz, 1H), 7.61 (dt, J=8.6, 1.0 Hz, 1H),7.53 (ddd, J=8.7, 7.0, 2.1 Hz, 1H), 7.21-7.07 (m, 1H), 6.63 (d, J=1.1Hz, 1H), 4.50 (s, 2H), 4.48-4.37 (m, 1H), 4.07-3.95 (m, 2H), 3.87-3.75(m, 2H), 3.75-3.67 (m, 1H), 3.65-3.60 (m, 1H), 3.56-3.42 (m, 4H),3.12-3.02 (m, 1H), 2.99-2.78 (m, 2H), 2.62 (d, J=4.6 Hz, 3H), 2.21-2.00(m, 7H), 1.98-1.88 (m, 2H). LCMS M/Z (M+H) 503.3. Example 15: ¹H NMR(400 MHz, DMSO-d₆) δ 9.44 (d, J=1.0 Hz, 1H), 7.95 (d, J=4.8 Hz, 1H),7.61 (dt, J=8.5, 1.1 Hz, 1H), 7.53 (ddd, J=8.9, 7.0, 2.1 Hz, 1H),7.19-7.08 (m, 1H), 6.67-6.59 (m, 1H), 4.50 (s, 2H), 4.46-4.47 (m, 1H),4.01 (dd, J=10.9, 4.8 Hz, 2H), 3.87-3.77 (m, 2H), 3.73-3.66 (m, 1H),3.65-3.58 (m, 1H), 3.54-3.42 (m, 4H), 3.11-3.03 (m, 1H), 2.94 (t, J=5.6Hz, 2H), 2.62 (d, J=4.6 Hz, 3H), 2.18-2.00 (m, 7H), 1.96-1.88 (m, 2H).LCMS M/Z (M+H) 503.3.

Example 16 (Procedure O)1-(3-(isoquinolin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 35 mg, 0.11 mmol) and 4-isoquinolylboronic acid (37 mg,0.21 mmol) in dioxane (0.7 mL) and water (0.2 mL) was added K₃PO₄.H₂O(63 mg, 0.27 mmol),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (4.8 mg, 0.0053 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (2.6 mg, 0.0053mmol). The mixture was stirred at 100° C. for 5 h under a nitrogenatmosphere. The reaction mixture was then cooled to room temperature andconcentrated in vacuo. The crude residue was dissolved indichloromethane (5 mL), dried over anhydrous MgSO₄, filtered throughcelite and concentrated in vacuo. The mixture obtained was purified byreverse phase chromatography (acetonitrile 5-50%/0.1% ammonium hydroxidein water) to give the title compound (38.2 mg, 90%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.50-8.42 (m, 2H), 8.20 (d, J=8.0Hz, 1H), 7.89-7.80 (m, 1H), 7.77-7.71 (m, 1H), 4.56-4.49 (m, 2H),4.49-4.38 (m, 1H), 4.06-3.97 (m, 2H), 3.88-3.77 (m, 2H), 3.58-3.46 (m,2H), 3.00-2.78 (m, 2H), 2.20-2.05 (m, 4H), 2.01 (s, 1H), 1.98-1.88 (m,2H). LCMS M/Z (M+H) 377.

Example 17 (Procedure P)5-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-methyl-1,4-dihydroisoquinolin-3(2H)-one

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 80 mg, 0.24 mmol) and bis(pinacolato)diboron (124 mg,0.488 mmol) in dioxane (1.2 mL) was added KOAc (72 mg, 0.73 mmol),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (5.9 mg, 0.0073 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (7.1 mg, 0.015mmol). The mixture was stirred at 80° C. for 16 h under a nitrogenatmosphere. The reaction mixture was cooled to room temperature and5-chloro-2-methyl-1,4-dihydroisoquinolin-3-one (26 mg, 0.13 mmol),K₃PO₄.H₂O (78 mg, 0.33 mmol), water (0.3 mL) and(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (5.9 mg, 0.0073 mmol) were added. The reaction mixturewas stirred at 90° C. for 4 h under a nitrogen atmosphere. The reactionmixture was then cooled to room temperature and concentrated in vacuo.The crude residue was dissolved in dichloromethane (5 mL), dried overanhydrous MgSO₄, filtered through celite and concentrated in vacuo. Themixture obtained was purified by SFC (Supercritical CO₂ 5-40%/MeOH (0.1%NH₃H₂O)) to give the title compound (28.3 mg, 28%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 7.37-7.19 (m, 3H), 4.55 (s, 2H), 4.42 (s, 2H),4.40-4.31 (m, 1H), 4.02-3.94 (m, 2H), 3.78 (dt, J=14.7, 5.8 Hz, 2H),3.65 (d, J=3.9 Hz, 2H), 3.54-3.43 (m, 2H), 2.96 (s, 3H), 2.93-2.73 (m,2H), 2.13-1.98 (m, 5H), 1.87 (dd, J=12.7, 5.2 Hz, 2H). LCMS M/Z (M+H)409.

Example 18 (Procedure Q)7-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(4-methoxyphenyl)isoindolin-1-one

Step 1:7-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoindolin-1-one

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 350 mg, 1.07 mmol) and bis(pinacolato)diboron (542 mg,2.13 mmol) in dioxane (5.3 mL) was added KOAc (314 mg, 3.20 mmol),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (26 mg, 0.032 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (31 mg, 0.064mmol). The mixture was stirred at 80° C. for 16 h under a nitrogenatmosphere. The reaction mixture was cooled to room temperature and7-bromoisoindolin-1-one (113 mg, 0.533 mmol), K₃PO₄.H₂O (313 mg, 1.33mmol), water (1.3 mL) and(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (26 mg, 0.032 mmol) were added. The reaction mixturewas stirred at 90° C. for 4 h under a nitrogen atmosphere. The reactionmixture was then cooled to room temperature and concentrated in vacuo.The crude residue was dissolved in dichloromethane (20 mL), dried overanhydrous MgSO₄, filtered through celite and concentrated in vacuo. Themixture obtained was purified by silica gel chromatography(MeOH/iPrOAc=1:10 to 1:3) to give the title compound (144 mg, 36%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆, 23/24 H) δ 7.66-7.40 (m, 3H),6.06-5.94 (m, 1H), 4.48 (d, J=9.5 Hz, 2H), 4.62-4.41 (m, 1H), 4.18 (dd,J=36.7, 11.6 Hz, 2H), 3.99-3.77 (m, 2H), 3.59-3.47 (m, 3H), 2.82 (dt,J=24.3, 5.9 Hz, 2H), 2.43-2.30 (m, 2H), 2.17-2.06 (m, 3H), 1.93 (d,J=13.2 Hz, 2H). LCMS M/Z (M+H) 381.

Step 2:7-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(4-methoxyphenyl)isoindolin-1-one

To a solution of7-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoindolin-1-one(30 mg, 0.079 mmol) in dioxane (0.46 mL) was added 4-bromoanisole (14mg, 0.075 mmol), N,N′-dimethylethylenediame (1.0 μL, 0.0095 mmol),copper(I) iodide (1.8 mg, 0.0095 mmol) and K₂CO₃ (44 mg, 0.32 mmol). Themixture was stirred at 101° C. for 24 h under a nitrogen atmosphere. Thereaction mixture was then cooled to room temperature, diluted withdichloromethane (5 mL), filtered through celite and concentrated invacuo. The mixture obtained was purified by reverse phase chromatography(acetonitrile 20-60%/0.1% formic acid in water) to give the titlecompound (32.1 mg, 84%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.80-7.70 (m, 2H), 7.72-7.61 (m, 2H), 7.43 (ddd, J=11.2, 6.7, 1.9 Hz,1H), 7.04-6.96 (m, 2H), 5.00 (s, 2H), 4.40 (s, 1H), 4.38-4.31 (m, 2H),4.02-3.94 (m, 2H), 3.77 (s, 3H), 3.73 (t, J=6.1 Hz, 2H), 3.48 (dd,J=13.7, 10.4 Hz, 2H), 2.94-2.72 (m, 2H), 2.16-2.03 (m, 4H), 1.98 (s,1H), 1.88 (d, J=12.9 Hz, 2H). LCMS M/Z (M+H) 487.

Example 19 (Procedure R)1-(3-(6-(4-methoxyphenyl)-1H-indol-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

Step 1: 6-(4-methoxyphenyl)-1H-indole

To a solution of 6-bromo-1H-indole (150 mg, 0.765 mmol) and(4-methoxyphenyl)boronic acid (151 mg, 0.995 mmol) in dioxane (2.6 mL)and water (0.6 mL) was added K₃PO₄.H₂O (545 mg, 2.30 mmol),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (25 mg, 0.031 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (15 mg, 0.031mmol). The reaction mixture was stirred at 85° C. for 16 h under anitrogen atmosphere. The reaction mixture was then cooled to roomtemperature and concentrated in vacuo. The crude residue was dissolvedin dichloromethane (10 mL), dried over anhydrous MgSO₄, filtered throughcelite and concentrated in vacuo. The mixture obtained was purified bysilica gel chromatography (iPrOAc/Heptane=1:19 to 1:9) to give the titlecompound (134 mg, 78%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.17 (s, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.62-7.48 (m, 3H), 7.34 (dd,J=8.2, 1.6 Hz, 1H), 7.22 (dd, J=3.2, 2.4 Hz, 1H), 7.03-6.94 (m, 2H),6.56 (ddd, J=3.2, 2.1, 1.0 Hz, 1H), 3.86 (s, 3H). LCMS M/Z (M+H) 224.

Step 2:1-(3-(6-(4-methoxyphenyl)-1H-indol-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 50 mg, 0.15 mmol) in toluene (0.76 mL) was added6-(4-methoxyphenyl)-1H-indole (51 mg, 0.23 mmol), K₃PO₄ (77 mg, 0.35mmol), copper(I) iodide (29 mg, 0.15 mmol) and(trans)-1,2-diaminocyclohexane (18 mg, 0.15 mmol). The mixture wasstirred at 110° C. for 16 h under a nitrogen atmosphere. The reactionmixture was then cooled to room temperature, diluted withdichloromethane (5 mL), filtered through celite and concentrated invacuo. The mixture obtained was purified by reverse phase chromatography(acetonitrile 30-70%/0.1% ammonium hydroxide in water) to give the titlecompound (49.6 mg, 69%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.05-7.90 (m, 1H), 7.69 (dd, J=8.2, 2.1 Hz, 1H), 7.62-7.54 (m, 2H),7.58-7.47 (m, 1H), 7.40 (dd, J=8.2, 1.6 Hz, 1H), 7.08-6.98 (m, 2H),6.73-6.67 (m, 1H), 4.52 (d, J=11.4 Hz, 2H), 4.41 (tt, J=11.0, 4.5 Hz,1H), 4.00 (ddd, J=9.3, 4.8, 2.5 Hz, 2H), 3.86-3.77 (m, 5H), 3.50 (td,J=12.0, 2.4 Hz, 2H), 2.95-2.75 (m, 2H), 2.12 (s, 2H), 2.10-1.99 (m, 3H),1.93 (dd, J=12.8, 4.2 Hz, 2H). LCMS M/Z (M+H) 471.

Example 20 (Procedure S)1-(3-(2-(2,4-dimethylphenyl)imidazo[1,2-a]pyridin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

Step 1:8-bromo-2-(2,4-dimethylphenyl)imidazo[1,2-a]pyridine

To a solution of 3-bromopyridin-2-amine (200 mg, 1.16 mmol) in2-propanol (2.3 mL) was added 2-bromo-1-(2,4-dimethylphenyl)ethanone(315 mg, 1.39 mmol). The mixture was stirred at 75° C. for 72 h. Thereaction mixture was then cooled to room temperature and concentrated invacuo. The crude residue was partitioned between DCM (50 mL) andsaturated aqueous NaHCO₃ solution (50 mL) and the two phases wereseparated. The aqueous layer was extracted with DCM (2×50 mL). Thecombined organic layers were dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The mixture obtained was purified by silica gelchromatography (iPrOAc/Heptane=1:9) to give the title compound (242 mg,70%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (dd,J=6.7, 1.1 Hz, 1H), 7.84-7.77 (m, 1H), 7.74 (s, 1H), 7.43 (dd, J=7.3,1.0 Hz, 1H), 7.13-7.06 (m, 2H), 6.66 (dd, J=7.3, 6.7 Hz, 1H), 2.52 (s,3H), 2.36 (s, 3H). LCMS M/Z (M+H) 301.

Step 2:1-(3-(2-(2,4-dimethylphenyl)imidazo[1,2-a]pyridin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 50 mg, 0.15 mmol) and bis(pinacolato)diboron (77 mg,0.30 mmol) in dioxane (0.76 mL) was added KOAc (45 mg, 0.46 mmol),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (3.7 mg, 0.0046 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (4.4 mg, 0.0091mmol). The mixture was stirred at 80° C. for 16 h under a nitrogenatmosphere. The reaction mixture was cooled to room temperature and8-bromo-2-(2,4-dimethylphenyl)imidazo[1,2-a]pyridine (23 mg, 0.076mmol), K₃PO₄.H₂O (38 mg, 0.17 mmol), water (0.3 mL) and(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (3.7 mg, 0.0046 mmol) were added. The reaction mixturewas stirred at 90° C. for 4 h under a nitrogen atmosphere. The reactionmixture was then cooled to room temperature and concentrated in vacuo.The crude residue was dissolved in dichloromethane (5 mL), dried overanhydrous MgSO₄, filtered through celite and concentrated in vacuo. Themixture obtained was purified by reverse phase chromatography(acetonitrile 20-60%/0.1% ammonium hydroxide in water) to give the titlecompound (21.3 mg, 30%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.58 (ddd, J=6.7, 3.2, 1.2 Hz, 1H), 8.25 (s, 1H), 8.06-7.81 (m, 1H),7.50-7.36 (m, 1H), 7.14-7.05 (m, 2H), 6.97 (q, J=7.0 Hz, 1H), 4.87 (s,1H), 4.76 (s, 1H), 4.39 (tq, J=10.7, 4.6 Hz, 1H), 4.00 (dd, J=10.3, 4.6Hz, 2H), 3.79 (dt, J=8.9, 5.7 Hz, 2H), 3.50 (tt, J=11.8, 1.8 Hz, 2H),2.95-2.75 (m, 2H), 2.52 (s, 3H), 2.31 (s, 3H), 2.19-2.03 (m, 4H),1.96-1.84 (m, 3H). LCMS M/Z (M+H) 470.

Example 21 (Procedure T)1-(3-(2-(4-methoxyphenyl)benzo[d]oxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

Step 1: 4-bromo-2-(4-methoxyphenyl)benzo[d]oxazole

To a solution of 3-bromo-2-nitro-phenol (120 mg, 0.550 mmol) in toluene(1.4 mL) was added (4-methoxyphenyl)methanol (190 mg, 1.38 mmol) and1,1′-bis(diphenylphosphino)ferrocene (9.2 mg, 0.016 mmol). The mixturewas stirred at 150° C. for 24 h in a sealed vial under a nitrogenatmosphere. The reaction mixture was then cooled to room temperature,diluted with dichloromethane (10 mL), filtered through celite andconcentrated in vacuo. The mixture obtained was purified by silica gelchromatography (acetone/heptane=1:19 to 1:9) to give the title compound(69.2 mg, 41%) as a pink solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.29-8.20(m, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.19 (t, J=8.0 Hz, 1H), 7.07-6.98 (m,2H), 3.90 (s, 3H). LCMS M/Z (M+H) 305.

Step 2:1-(3-(2-(4-methoxyphenyl)benzo[d]oxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 50 mg, 0.15 mmol) and bis(pinacolato)diboron (77 mg,0.30 mmol) in dioxane (0.76 mL) was added KOAc (45 mg, 0.46 mmol),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (3.7 mg, 0.0046 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (4.4 mg, 0.0091mmol). The mixture was stirred at 80° C. for 16 h under a nitrogenatmosphere. The reaction mixture was cooled to room temperature and4-bromo-2-(4-methoxyphenyl)-1,3-benzoxazole (27 mg, 0.088 mmol),K₃PO₄.H₂O (47 mg, 0.20 mmol), water (0.3 mL) and(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (3.7 mg, 0.0046 mmol) were added. The reaction mixturewas stirred at 90° C. for 4 h under a nitrogen atmosphere. The reactionmixture was then cooled to room temperature and concentrated in vacuo.The crude residue was dissolved in dichloromethane (5 mL), dried overanhydrous MgSO₄, filtered through celite and concentrated in vacuo. Themixture obtained was purified by reverse phase chromatography(acetonitrile 30-70%/0.1% formic acid in water) to give the titlecompound (28.9 mg, 40%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.29-8.15 (m, 2H), 7.73 (ddd, J=8.1, 4.8, 1.1 Hz, 1H), 7.63 (td, J=7.9,1.0 Hz, 1H), 7.44 (td, J=8.0, 4.4 Hz, 1H), 7.22-7.12 (m, 2H), 4.86 (d,J=10.1 Hz, 2H), 4.40 (td, J=11.2, 4.5 Hz, 1H), 4.05-3.96 (m, 2H), 3.88(d, J=1.3 Hz, 3H), 3.83 (dt, J=12.0, 5.7 Hz, 2H), 3.50 (tt, J=11.5, 1.8Hz, 2H), 2.95-2.75 (m, 2H), 2.20-2.03 (m, 5H), 1.94-1.85 (m, 2H). LCMSM/Z (M+H) 473.

Example 22 (Procedure U)3-(5-acetyl-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-N-(3-cyanophenyl)benzamide

Step 1: methyl3-(5-acetyl-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)benzoate

A solution of1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate F, 2.3 g, 7.3 mmol) and (3-(methoxycarbonyl)phenyl)boronicacid (2.0 g, 11 mmol) in dioxane (20 mL) was charged with aqueous sodiumcarbonate solution (1.0 M, 20 mL) and heated at 120° C. for 20 minutes.The mixture was then diluted with ethyl acetate and water and the layerswere partitioned and separated. The organic layer was washed once withwater, dried over anhydrous magnesium sulfate, filtered and concentratedin vacuo. The crude residue was purified by silica gel chromatography(dichloromethane/methanol=100:1 to 10:1) to give the title compound (2.6g, 7.0 mmol, 96% yield). LCMS M/Z (M+H) 370.

Step 2:3-(5-acetyl-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)benzoicacid

A solution of methyl3-(5-acetyl-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)benzoate(3.2 g, 8.7 mmol) in THF (20 mL) and MeOH (10 mL) was charged withaqueous lithium hydroxide solution (2.0 M, 10 mL) and stirred at roomtemperature overnight. The mixture was then concentrated in vacuo toremove the organic solvents. The pH of the resulting aqueous mixture wasadjusted to pH=4 by titration with aqueous hydrochloric acid solution(1.0 M). The precipitate was then collected by filtration, washed withwater, and dried under vacuum to afford the title compound (2.9 g, 8.2mmol, 92% yield). LCMS M/Z (M+H) 356.

Step 3:3-(5-acetyl-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-N-(3-cyanophenyl)benzamide

A solution of3-(5-acetyl-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)benzoicacid (20 mg, 0.056 mmol) in DMF (0.5 mL) was charged with1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (44 mg, 0.11 mmol) and diisopropylethylamine(15 mg, 0.11 mmol), then stirred at room temperature for 5 min. To themixture was added 3-aminobenzonitrile (13 mg, 0.11 mmol). After stirringat room temperature for an additional 1 h, the reaction mixture waspurified by reverse phase preparative HPLC (acetonitrile 5-50%/0.1%ammonium hydroxide in water) to give the title compound (23 mg, 0.055mmol, 90%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.27 (ddd, J=2.8,2.3, 1.1 Hz, 1H), 8.21-8.13 (m, 1H), 8.11-8.02 (m, 1H), 7.95-7.87 (m,1H), 7.86-7.79 (m, 1H), 7.68-7.55 (m, 3H), 5.07-4.93 (m, 1H), 4.71 (d,J=2.6 Hz, 2H), 4.16-3.99 (m, 2H), 3.97-3.71 (m, 4H), 2.95-2.84 (m, 1H),2.77 (d, J=6.0 Hz, 1H), 2.42-2.30 (m, 2H), 2.17-2.00 (m, 3H). LCMS M/Z(M+H) 456.2.

Example 23 (Procedure V)5-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-cyclopentyl-1,2-dihydroisoquinolin-3(4H)-one

Step 1: 2-(2-chlorophenyl)-N-cyclopentylacetamide

To a solution of 2-(2-chlorophenyl)acetic acid (17.5 g, 102.59 mmol) inDMF (100 mL) was added HATU (58.51 g, 153.88 mmol),N,N-diisopropylethylamine (50.86 mL, 307.76 mmol) and cyclopentylamine(12.06 mL, 123.1 mmol). The reaction mixture was stirred at roomtemperature for 16 h under a nitrogen atmosphere. The reaction solutionwas poured into water (200 mL) and extracted with EtOAc (150 mL×3). Thecombined organic layers were washed with brine (200 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica gel chromatography (petroleum ether/EtOAc=3:1) togive the title compound (20 g, 82%) as a white solid.

Step 2: 5-chloro-2-cyclopentyl-1,2-dihydroisoquinolin-3(4H)-one

A mixture of 2-(2-chlorophenyl)-N-cyclopentylacetamide (3 g, 12.62mmol), paraformaldehyde (1.89 g, 63.1 mmol), methanesulfonic acid (25mL, 384.98 mmol) and phosphorus pentoxide (3.0 g, 21.14 mmol) was heatedto 80° C. for 2 h. The reaction mixture was poured into ice water (150mL), neutralized with Na₂CO₃, and then extracted with EtOAc (100 mL×3).The combined organic layers were washed with brine (100 mL×3), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (petroleumether/EtOAc=4:1) to give the title compound (600 mg, 19%) as a greensolid. LCMS M/Z (M+H) 250.

Step 3:1-(1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 300 mg, 0.91 mmol) in 1,4-dioxane (4 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (26 mg, 0.05mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (22 mg, 0.03 mmol), KOAc (269 mg, 2.74 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (464 mg,1.83 mmol). The mixture was heated to 80° C. for 3 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 376.

Step 4:5-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-cyclopentyl-1,2-dihydroisoquinolin-3(4H)-one

To the above step cooled solution was added5-chloro-2-cyclopentyl-1,2-dihydroisoquinolin-3(4H)-one (113 mg, 0.45mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (23 mg, 0.03 mmol), K₃PO₄ (240 mg, 1.13 mmol), 1,4-dioxane(1 mL) and water (1 mL). The reaction mixture was heated to 90° C. for 1h under a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. Water (100 mL) was addedand extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine (50 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (acetonitrile 30-60%/0.05% NH₄OH in water) to give thetitle compound (86 mg, 20%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 7.40 (d, J=8.0 Hz, 1H), 7.34-7.29 (m, 1H), 7.24 (d, J=6.8 Hz, 1H),4.88-4.78 (m, 1H), 4.47-4.31 (m, 5H), 4.04-3.95 (m, 2H), 3.83-3.73 (m,2H), 3.71-3.65 (m, 2H), 3.49 (t, J=12.0 Hz, 2H), 2.94-2.75 (m, 2H),2.12-2.01 (m, 5H), 1.92-1.83 (m, 2H), 1.80-1.64 (m, 4H), 1.62-1.52 (m,4H). LCMS M/Z (M+H) 463.

Example 245-(8-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-4-fluoroisoquinolin-3-yl)-N-methylpicolinamide

Step 1: 8-chloro-4-fluoroisoquinolin-3(2H)-one

To a solution of 8-chloroisoquinolin-3(2H)-one (600 mg, 3.34 mmol) inTHF (10 mL) was added1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (1.36 g, 3.84 mmol). The reaction was stirred atroom temperature for 16 h. DCM (80 mL) was added and washed with water(20 mL×2). The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to give the title compound (650 mg, crude) asa yellow solid that required no further purification. LCMS M/Z (M+H)198.

Step 2: 8-chloro-4-fluoroisoquinolin-3-yl trifluoromethanesulfonate

To a solution of 8-chloro-4-fluoroisoquinolin-3(2H)-one (200 mg, 1.01mmol) in DCM (4 mL) at 0° C. was added triethylamine (0.42 mL, 3.04mmol) and trifluoromethanesulfonic anhydride (0.42 mL, 2.53 mmol). Thereaction was stirred at room temperature for 12 h and concentrated invacuo. The crude residue was purified by silica gel chromatography(petroleum ether/EtOAc=10:1) to give the title compound (100 mg, 30%) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.34 (s, 1H), 8.28 (d, J=8.4Hz, 1H), 8.13-8.07 (m, 1H), 8.06-8.00 (m, 1H). LCMS M/Z (M+H) 330.

Step 3: 5-(8-chloro-4-fluoroisoquinolin-3-yl)-N-methylpicolinamide

To a solution of 8-chloro-4-fluoroisoquinolin-3-yltrifluoromethanesulfonate (500 mg, 1.52 mmol) in 1,4-dioxane (4 mL) andwater (1 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (111 mg,0.15 mmol), Na₂CO₃ (482 mg, 4.55 mmol) andN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide(398 mg, 1.52 mmol). The mixture was irradiated in a microwave at 70° C.for 0.5 h. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. The crude residue was purifiedby silica gel chromatography (petroleum ether/EtOAc=3:1) to give thetitle compound (300 mg, 63%) as a yellow solid. LCMS M/Z (M+H) 316.

Step 4:5-(4-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)-N-methylpicolinamide

To a solution of5-(8-chloro-4-fluoroisoquinolin-3-yl)-N-methylpicolinamide (150 mg, 0.48mmol) in 1,4-dioxane (3 mL) was added(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (23 mg, 0.05 mmol)andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (37 mg, 0.05 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (181 mg,0.71 mmol) and KOAc (93 mg, 0.95 mmol). The mixture was heated to 80° C.for 1 h under a nitrogen atmosphere. After cooling the reaction to roomtemperature, the reaction mixture was used to the next step directlywithout further purification. LCMS M/Z (M+H) 408.

Step 5:5-(8-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-4-fluoroisoquinolin-3-yl)-N-methylpicolinamide

To the above step cooled solution was added1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 118 mg, 0.36 mmol),(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (17 mg, 0.04 mmol)andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (28 mg, 0.04 mmol) and Na₂CO₃ (76 mg, 0.72 mmol),1,4-dioxane (2 mL) and water (1 mL). The reaction mixture was heated to60° C. for 16 h under a nitrogen atmosphere. After cooling to roomtemperature, the mixture was filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile29-59%/0.2% formic acid in water) to give the title compound (28 mg,11%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.89 (s, 1H), 9.29(s, 1H), 8.91 (d, J=4.8 Hz, 1H), 8.65 (d, J=8.0 Hz, 1H), 8.27-8.18 (m,2H), 8.10-7.99 (m, 1H), 7.90-7.76 (m, 1H), 4.60 (s, 2H), 4.54-4.40 (m,1H), 4.09-3.95 (m, 2H), 3.92-3.75 (m, 2H), 3.53 (t, J=11.6 Hz, 2H),3.03-2.79 (m, 2H), 2.87 (d, J=4.4 Hz, 3H), 2.17-2.03 (m, 5H), 2.02-1.90(m, 2H). LCMS M/Z (M+H) 529.

Example 253-(6-(difluoromethyl)-7-(1-methyl-1H-pyrazol-4-yl)isoquinolin-4-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

Step 1: N-(3-bromo-4-chlorobenzylidene)-2,2-dimethoxyethanamine

To a solution of 3-bromo-4-chlorobenzaldehyde (18.0 g, 82.02 mmol) intoluene (200 mL) was added 2,2-dimethoxyethanamine (10.35 g, 98.42mmol). The mixture was heated to 110° C. for 16 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas concentrated in vacuo to give the title compound (25.0 g, crude) asyellow oil that required no further purification.

Step 2: N-(3-bromo-4-chlorobenzyl)-2,2-dimethoxyethanamine

To a solution of N-(2-bromo-4-chlorobenzylidene)-2,2-dimethoxyethanamine(25.0 g, 81.54 mmol) in MeOH (150 mL) at 0° C. was added sodiumborohydride (2.47 g, 65.24 mmol) portionwise. The mixture was stirred at28° C. for 2 h under a nitrogen atmosphere and concentrated in vacuo.Water (200 mL) was added and extracted with DCM (200 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (25.0 g, crude) ascolorless oil that required no further purification. LCMS M/Z (M+H) 308.

Step 3:N-(3-bromo-4-chlorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide

To a solution of N-(3-bromo-4-chlorobenzyl)-2,2-dimethoxyethanamine(27.8 g, 90.08 mmol) in DCM (200 mL) at 0° C. was added4-methylbenzene-1-sulfonyl chloride (17.17 g, 90.08 mmol),N,N-dimethylpyridin-4-amine (550 mg, 4.5 mmol) and triethylamine (24.97mL, 180.17 mmol). The mixture was stirred at 28° C. for 16 h under anitrogen atmosphere. Water (150 mL) was added and extracted with DCM(150 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=20:1) togive the title compound (35 g, 84%) as colorless oil. LCMS M/Z (M+H)462.

Step 4: 7-bromo-6-chloroisoquinoline

To a solution of aluminum trichloride (44.66 g, 334.93 mmol) in1,2-dichloroethane (250 mL) at 0° C. was addedN-(3-bromo-4-chlorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide(31.0 g, 66.99 mmol) in 1,2-dichloroethane (250 mL) dropwise. Themixture was stirred at 28° C. for 16 h under a nitrogen atmosphere. Themixture was quenched with ice-water (130 mL) and extracted with DCM (130mL×3). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified bysilica gel chromatography (petroleum ether/EtOAc=10:1) to give the titlecompound (11.0 g, 68%) as a white solid. LCMS M/Z (M+H) 242.

Step 5: 6-chloro-7-(1-methyl-1H-pyrazol-4-yl)isoquinoline

To a solution of 7-bromo-6-chloroisoquinoline (12.1 g, 49.9 mmol) in1,4-dioxane (100 mL) and water (10 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.65 g,4.99 mmol), Na₂CO₃ (13.22 g, 124.74 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(15.57 g, 74.85 mmol). The mixture was heated to 70° C. for 3 h under anitrogen atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=1:1) togive the title compound (11.5 g, 95%) as a brown solid. LCMS M/Z (M+H)244.

Step 6: 7-(1-methyl-1H-pyrazol-4-yl)isoquinoline-6-carbaldehyde

To a solution of 6-chloro-7-(1-methyl-1H-pyrazol-4-yl)isoquinoline (2.0g, 8.21 mmol) in DMSO (15 mL) was added palladium(II) acetate (92 mg,0.41 mmol), 1,2-bis(diphenylphosphino)ethane (327 mg, 0.82 mmol),potassium formate (1.38 g, 16.41 mmol) and tert-butyl isocyanide (1.11mL, 9.85 mmol). The mixture was heated to 120° C. for 6 h under anitrogen atmosphere. After cooling the reaction to room temperature,sat. aq. NaHCO₃ (50 mL) was added and the mixture stirred for anadditional 30 min. The solution was extracted with DCM (50 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=1:1) to give the title compound(1.0 g, 51%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s,1H), 9.41 (s, 1H), 8.57 (d, J=6.0 Hz, 1H), 8.51 (s, 1H), 8.26 (s, 1H),8.13 (s, 1H), 8.04 (d, J=5.6 Hz, 1H), 7.82 (s, 1H), 3.94 (s, 3H). LCMSM/Z (M+H) 238.

Step 7: 6-(difluoromethyl)-7-(1-methyl-1H-pyrazol-4-yl)isoquinoline

To a solution of 7-(1-methyl-1H-pyrazol-4-yl)isoquinoline-6-carbaldehyde(450 mg, 1.9 mmol) in DCM (10 mL) at 0° C. was addeddiethylaminosulfurtrifluoride (0.75 mL, 5.69 mmol). The mixture wasstirred at room temperature for 21 h. The mixture was poured into sat.aq. NaHCO₃ (10 mL) at 0° C. and extracted with EtOAc (20 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=2:3) to give the title compound(160 mg, 33%) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 9.31 (s, 1H),8.60 (d, J=6.0 Hz, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.76 (d, J=5.6 Hz,1H), 7.72 (s, 1H), 7.63 (s, 1H), 6.79 (d, J=54.8 Hz, 1H), 4.03 (s, 3H).

Step 8:4-bromo-6-(difluoromethyl)-7-(1-methyl-1H-pyrazol-4-yl)isoquinoline

To a solution of6-(difluoromethyl)-7-(1-methyl-1H-pyrazol-4-yl)isoquinoline (160 mg, 0.6mmol) in AcOH (1 mL) was added N-bromosuccinimide (109 mg, 0.6 mmol).The mixture was heated to 90° C. for 2 h under a nitrogen atmosphere.After cooling to room temperature, the mixture was concentrated invacuo. DCM (10 mL) was added and washed with water (10 mL×3) and brine(10 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=100:1) to give the title compound (95 mg, 45%)as a light yellow solid. LCMS M/Z (M+H) 338.

Step 9: tert-butyl1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate G, 500 mg, 1.29 mmol) in 1,4-dioxane (5 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (62 mg, 0.13mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (102 mg, 0.13 mmol), KOAc (381 mg, 3.88 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (657 mg,2.59 mmol). The mixture was heated to 80° C. for 3 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 434.

Step 10: tert-butyl3-(6-(difluoromethyl)-7-(1-methyl-1H-pyrazol-4-yl)isoquinolin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To the above step cooled solution was added4-bromo-6-(difluoromethyl)-7-(1-methyl-1H-pyrazol-4-yl)isoquinoline (95mg, 0.28 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl(13 mg, 0.028 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (22 mg, 0.028 mmol), Na₂CO₃ (89 mg, 0.84 mmol),1,4-dioxane (5 mL) and water (2 mL). The reaction mixture was heated to60° C. for 16 h under a nitrogen atmosphere. After cooling to roomtemperature, the mixture was filtered and concentrated in vacuo. DCM (50mL) was added and washed with water (30 mL×3) and brine (20 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The crude residue was purified by silica gel chromatography(DCM/MeOH=100:1) to give the title compound (70 mg, 10%) as a yellowsolid. LCMS M/Z (M+H) 565.

Step 11:6-(difluoromethyl)-7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoquinoline

To a solution of tert-butyl3-(6-(difluoromethyl)-7-(1-methyl-1H-pyrazol-4-yl)isoquinolin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(70 mg, 0.12 mmol) in DCM (1 mL) at 0° C. was added trifluoroacetic acid(1 mL, 13.42 mmol). The mixture was stirred at room temperature for 12 hand concentrated in vacuo to give the title compound (50 mg, crude) asbrown oil that required no further purification. LCMS M/Z (M+H) 465.

Step 12:3-(6-(difluoromethyl)-7-(1-methyl-1H-pyrazol-4-yl)isoquinolin-4-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

To a solution of6-(difluoromethyl)-7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoquinoline(50 mg, 0.11 mmol) in DCM (5 mL) was added triethylamine (0.04 mL, 0.32mmol) and N-methyl-1H-imidazole-1-carboxamide (20 mg, 0.16 mmol). Thereaction was stirred at room temperature for 1 h. DCM (50 mL) was addedand washed with water (50 mL×3) and brine (20 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile30-60%/0.05% NH₄OH in water) to give the title compound (32 mg, 57%) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H), 9.12 (s, 1H),8.59 (s, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 7.27 (t, J=56.0Hz, 1H), 6.66-6.60 (m, 1H), 4.51-4.44 (m, 3H), 4.05-3.98 (m, 2H), 3.95(s, 3H), 3.75-3.67 (m, 2H), 3.57-3.48 (m, 2H), 2.86-2.80 (m, 2H), 2.54(d, J=4.4 Hz, 3H), 2.20-2.07 (m, 2H), 1.97-1.92 (m, 2H). LCMS M/Z (M+H)522.

Examples 26 & 27(S)-1-(3-(3-(1-methyl-1H-pyrazol-4-yl)quinolin-5-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanoneand(S)-1-(3-(2-(1-methyl-1H-pyrazol-4-yl)quinolin-5-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1:(S)-1-(3-(quinolin-5-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of(S)-1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate E, 500 mg, 1.6 mmol) in 1,4-dioxane (10 mL) and water (2mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (116 mg, 0.2mmol), K₂CO₃ (446 mg, 3.2 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (609 mg, 1.9mmol). The mixture was heated to 120° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. DCM (50 mL) was added and washedwith water (50 mL×2) and brine (50 mL). The organic phase was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica gel chromatography (DCM/MeOH=20:1) to give thetitle compound (600 mg, 78%) as a yellow solid. LCMS M/Z (M+H) 363.

Step 2:(S)-5-(5-acetyl-1-(tetrahydrofuran-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)quinoline1-oxide

To a solution of(S)-1-(3-(quinolin-5-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(624 mg, 1.3 mmol) in DCM (10 mL) was added 3-chlorobenzenecarboperoxoicacid (334 mg, 1.9 mmol). The mixture was stirred at 26° C. for 4 h. DCM(80 mL) was added and washed with sat. aq. Na₂S₂O₃ (50 mL×3), water (50mL) and brine (50 mL). The organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (DCM/MeOH=20:1) to give the titlecompound (230 mg, 45%) as a yellow solid. LCMS M/Z (M+H) 379.

Step 3:(S)-1-(3-(3-bromoquinolin-5-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanoneand(S)-1-(3-(2-bromoquinolin-5-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of(S)-5-(5-acetyl-1-(tetrahydrofuran-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)quinoline1-oxide (145 mg, 0.4 mmol) and 4 Å molecular sieves in DCM (13 mL) wasadded tetrabutylammonium bromide (185 mg, 0.6 mmol). The mixture wasstirred at room temperature for 10 min and added 4-methylbenzenesulfonicanhydride (187 mg, 0.6 mmol). The mixture was stirred at roomtemperature for an additional 12 h. The mixture was filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=20:1) to give the mixture of title compounds(85 mg, 42%) as a yellow solid. LCMS M/Z (M+H) 441.

Step 4:(S)-1-(3-(3-(1-methyl-1H-pyrazol-4-yl)quinolin-5-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanoneand(S)-1-(3-(2-(1-methyl-1H-pyrazol-4-yl)quinolin-5-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of(S)-1-(3-(3-bromoquinolin-5-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanoneand(S)-1-(3-(2-bromoquinolin-5-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(80 mg, 0.15 mmol) in THF (5 mL) and water (1 mL) was added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (31mg, 0.15 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl(7 mg, 0.01 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (12 mg, 0.01 mmol), Na₂CO₃ (32 mg, 0.3 mmol). The mixturewas heated to 60° C. for 16 h under a nitrogen atmosphere. After coolingthe reaction to room temperature, the mixture was filtered andconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (acetonitrile 30-60%/0.1% NH₄OH in water) to give themixture of title compounds (50 mg, 62%) as a white solid which wasseparated by using chiral SFC (Chiralpak AD 250×30 mm I.D., 5 um;Supercritical CO₂/MEOH+NH₃/H₂O=45/55; 50 ml/min) to give(S)-1-(3-(3-(1-methyl-1H-pyrazol-4-yl)quinolin-5-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)etanone (5 mg, first peak) and(S)-1-(3-(2-(1-methyl-1H-pyrazol-4-yl)quinolin-5-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(21 mg, second peak). Example 26: ¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (s,1H), 9.10 (s, 1H), 8.36 (s, 1H), 8.02-7.95 (m, 1H), 7.99 (s, 1H),7.78-7.73 (m, 1H), 7.63-7.55 (m, 1H), 5.12-5.07 (m, 1H), 4.62-4.50 (m,2H), 4.12-4.00 (m, 3H), 3.92-3.76 (m, 3H), 3.90 (s, 1H), 2.97-2.84 (m,2H), 2.44-2.39 (m, 2H), 2.11-2.00 (m, 3H). LCMS M/Z (M+H) 443. Example27: ¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (d, J=8.8 Hz, 1H), 8.49 (s, 1H),8.18 (s, 1H), 7.96-7.91 (m, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.80-7.75 (m,1H), 7.56-7.46 (m, 1H), 5.09-5.03 (m, 1H), 4.50 (s, 2H), 4.12-4.01 (m,2H), 3.97-3.79 (m, 4H), 3.93 (s, 3H), 2.95-2.82 (m, 2H), 2.42-2.35 (m,2H), 2.10-2.00 (m, 3H). LCMS M/Z (M+H) 443.

Example 281-(3-(4-chloroisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: 8-bromo-4-chloroisoquinoline

To a solution of 8-bromoisoquinoline (12.2 g, 58.64 mmol) in AcOH (150mL) was added 1-chloropyrrolidine-2,5-dione (8.61 g, 64.5 mmol)portionwise. The mixture was heated to 117° C. for 2 h under a nitrogenatmosphere. After cooling the reaction to room temperature, water (150mL) was added and extracted with EtOAc (150 mL×3). The combined organiclayers were washed with sat. aq. NaHCO₃ (150 mL×3), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound(10.0 g, crude) as a yellow solid that required no further purification.LCMS M/Z (M+H) 242.

Step 2:4-chloro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline

To a solution of 8-bromo-4-chloroisoquinoline (500 mg, 2.06 mmol) in1,4-dioxane (8 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (151 mg,0.21 mmol), KOAc (607 mg, 6.19 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (785 mg,3.09 mmol). The mixture was heated to 80° C. for 4 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 290.

Step 3:1-(3-(4-chloroisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To the above step cooled solution was added1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 541 mg, 1.65 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (75 mg, 0.1mmol) and Na₂CO₃ (656 mg, 6.19 mmol), 1,4-dioxane (2 mL) and water (2mL). The reaction mixture was heated to 65° C. for 2 h under nitrogenatmosphere. After cooling to room temperature, the mixture was filteredand concentrated in vacuo. The crude residue was purified by reversephase chromatography (acetonitrile 20-50%/0.2% formic acid in water) togive the title compound (65 mg, 7%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 9.62-9.58 (m, 1H), 8.64-8.60 (m, 1H), 8.29-8.25 (m, 1H),7.90-7.85 (m, 1H), 7.68-7.63 (m, 1H), 4.62-4.45 (m, 2H), 4.35-4.24 (m,1H), 4.23-4.13 (m, 2H), 4.06-3.81 (m, 2H), 3.57 (t, J=12.0 Hz, 2H),2.95-2.85 (m, 2H), 2.44-2.41 (m, 2H), 2.21-2.08 (m, 3H), 1.98-1.94 (m,2H). LCMS M/Z M+H) 411.

Example 291-(3-(5-fluoroisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: 5-(benzyloxy)isoquinoline

To a stirred solution of isoquinolin-5-ol (1.0 g, 6.89 mmol) in DMF (30mL) at 0° C. was added NaH (60%, 303 mg, 7.58 mmol) and the mixture wasstirred for 30 min. Benzyl bromide (1.0 g, 5.86 mmol) was added dropwiseand the mixture stirred for an additional 1 h. The mixture was quenchedwith water (100 mL) and extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with brine (50 mL×3), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound(900 mg, crude) as yellow oil that required no further purification.LCMS M/Z (M+H) 236.

Step 2: 5-(benzyloxy)-8-bromoisoquinoline

To a solution of 5-(benzyloxy)isoquinoline (1.3 g, 5.53 mmol) and NaOAc(906 mg, 11.05 mmol) in AcOH (50 mL) at 26° C. was added bromine (0.28mL, 5.53 mmol) dropwise. The mixture was stirred at 26° C. for 16 h.Water (100 mL) was added and extracted with EtOAc (70 mL×3). Thecombined organic layers were washed with sat. aq. NaHCO₃ (100 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (petroleumether/EtOAc=4:1) to give the title compound (300 mg, 17%) as a whitesolid. LCMS M/Z (M+H) 314.

Step 3:1-(1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 2.3 g, 7.0 mmol) in 1,4-dioxane (40 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (200 mg, 0.42mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (165 mg, 0.21 mmol), KOAc (2.0 g, 21.0 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.56 g,14.0 mmol). The mixture was heated to 80° C. for 3 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 376.

Step 4:1-(3-(5-(benzyloxy)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To the above step cooled solution was added5-(benzyloxy)-8-bromoisoquinoline (1.1 g, 3.5 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (185 mg, 0.24 mmol), K₃PO₄ (1.98 g, 9.3 mmol), 1,4-dioxane(10 mL) and water (10 mL). The reaction mixture was heated to 90° C. for1 h under a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. Water (100 mL) was addedand extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine (50 mL×3), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=20:1) to give the title compound (1 g, 30%) asa brown solid. LCMS M/Z (M+H) 483.

Step 5:1-(3-(5-hydroxyisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-(5-(benzyloxy)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(1.0 g, 2.07 mmol) in MeOH (20 mL) was added Pd(OH)₂ (100 mg) and AcOH(2 drops). The mixture was stirred at 26° C. for 5 h under a hydrogenatmosphere (15 Psi). The mixture was filtered and concentrated in vacuo.The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give thetitle compound (400 mg, 49%) as a yellow solid. LCMS M/Z (M+H) 393.

Step 6:1-(3-(5-fluoroisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-(5-hydroxyisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(260 mg, 0.66 mmol) in toluene (7 mL) was added1,3-bis(2,6-di-i-propylphenyl)-2-chloroimidazolium chloride/cesiumfluoride admixture (1.69 g, 2.76 mmol). The mixture was stirred at 26°C. for 0.5 h and then heated to 110° C. for 24 h under a nitrogenatmosphere. After cooling to room temperature, the mixture was filteredand concentrated in vacuo. The crude residue was purified by Prep-TLC(DCM/MeOH=20:1) to give the title compound (3 mg, 1%) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ 9.71-9.67 (m, 1H), 8.67-8.53 (m, 1H),7.96-7.94 (m, 1H), 7.54-7.47 (m, 1H), 7.46-7.35 (m, 1H), 4.61-4.44 (m,2H), 4.33-4.22 (m, 1H), 4.21-4.12 (m, 2H), 4.02-3.83 (m, 2H), 3.60-3.53(m, 2H), 2.93-2.84 (m, 2H), 2.44-2.40 (m, 2H), 2.21-2.07 (m, 3H),1.98-1.94 (m, 2H). LCMS M/Z (M+H) 395.

Example 301-(3-(6-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: (2-bromo-4-chlorophenyl)methanamine

To a stirred solution of 2-bromo-4-chlorobenzonitrile (20.0 g, 138.6mmol) in anhydrous THF (200 mL) at 0° C. was added borane (277 mL, 277.2mmol, 1.0 M) in THF dropwise under a nitrogen atmosphere. The resultingmixture was stirred at 22° C. for 1 h and refluxed for 3 h. The reactionwas quenched with 2N HCl (300 mL) at 0° C. and then stirred at 70° C.for 1 h. After cooling to room temperature, the solution was extractedwith DCM (400 mL) and the aqueous phase was adjusted to pH=8 by using 2NNaOH. The mixture was extracted with DCM (300 mL×3). The organic layerwas dried over anhydrous Na₂SO₄ and concentrated in vacuo to give thetitle compound (12 g, 59%) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ7.55-7.53 (m, 1H), 7.34-7.29 (m, 1H), 7.28-7.23 (m, 1H), 3.86 (s, 2H).

Step 2: N-(2-bromo-4-chlorobenzyl)-2,2-dimethoxyacetamide

To a solution of (2-bromo-4-chloro-phenyl)methanamine (12 g, 54.4 mmol)in MeOH (80 mL) was added triethylamine (9.5 mL, 68.0 mmol) and methyldimethoxyacetate (8.0 g, 49.9 mmol). The mixture was heated to 80° C.for 20 h. After cooling to room temperature, the mixture wasconcentrated in vacuo. The crude residue was dissolved in EtOAc (150mL), washed with 1N HCl (150 mL), H₂O (150 mL), brine (150 mL). Theorganic phase was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to give the title compound (12 g, 68%) as a light yellow solid.¹H-NMR (400 MHz, CDCl₃) δ 7.58 (d, J=1.6 Hz, 1H), 7.33 (d, J=8.4 Hz,1H), 7.29-7.27 (m, 1H), 7.03 (s, 1H), 4.74 (s, 1H), 4.52 (d, J=6.4 Hz,2H), 3.41 (s, 6H).

Step 3: 8-bromo-6-chloroisoquinolin-3(2H)-one

To a solution of sulfuric acid (100 mL) at 0° C. was addedN-(2-bromo-4-chlorobenzyl)-2,2-dimethoxyacetamide (12.0 g, 37.2 mmol).The reaction was heated to 50° C. for 16 h. The reaction was poured intoice water (150 mL) and the mixture was basified with ammonium hydroxideto pH 8. The yellow precipitate was filtered off, washed with water, anddried in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=10:1) to give the title compound (3.7 g, 39%)as a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.10 (s, 1H), 7.93 (s,1H), 7.69 (d, J=2.0 Hz, 1H), 6.94 (s, 1H).

Step 4: 8-bromo-6-chloro-3-((triisopropylsilyl)oxy)isoquinoline

To a solution of 8-bromo-6-chloroisoquinolin-3(2H)-one (10 g, 38.7 mmol)in DMF (30 mL) at 0° C. was added imidazole (7.9 g, 116.1 mmol) andchlorotriisopropylsilane (12.4 mL, 58.0 mmol). The reaction was stirredat room temperature for 12 h. The reaction mixture was concentrated invacuo. The crude residue was dissolved in DCM (50 mL) and washed withH₂O (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether) to give the title compound (10 g, 62%)as yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ 9.15 (s, 1H), 7.59 (s, 1H),7.54 (s, 1H), 6.88 (s, 1H), 1.51-1.40 (m, 3H), 1.12 (d, J=7.2 Hz, 18H).

Step 5:6-chloro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((triisopropylsilyl)oxy)isoquinoline

To a solution of 8-bromo-6-chloro-3-((triisopropylsilyl)oxy)isoquinoline(9.0 g, 21.7 mmol) in 1,4-dioxane (9 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (1.6 g, 2.2mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (8.3g, 32.5 mmol) and 2-ethylhexanoyloxypotassium (11.9 g, 65.1 mmol). Themixture was heated to 70° C. for 1 h under a nitrogen atmosphere. Aftercooling the reaction to room temperature, the reaction mixture was usedto the next step directly without further purification. LCMS M/Z(M-TIPS+H) 306.

Step 6:1-(3-(6-chloro-3-((triisopropylsilyl)oxy)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To the above step cooled solution in 1,4-dioxane (60 mL) and water (12mL) was added1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 6.39 g, 19.49 mmol),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (1.58 g,2.16 mmol) and Na₂CO₃ (6.8 g, 64.9 mmol). The reaction mixture washeated to 70° C. for 4 h under nitrogen atmosphere. After cooling toroom temperature, the mixture was filtered and concentrated in vacuo.EtOAc (200 mL) was added and washed with water (120 mL×2). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel chromatography(DCM/MeOH=10:1) to give the title compound (2.6 g, 38% purity) as abrown solid. LCMS M/Z (M-TIPS+H) 427.

Step 7:1-(3-(6-chloro-3-hydroxyisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-(6-chloro-3-((triisopropylsilyl)oxy)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(2.6 g, 38% purity) in THF (10 mL) at 20° C. was added TBAF (22.3 ml,22.3 mmol, 1 M in THF). The reaction was stirred at room temperature for12 h. The reaction mixture was concentrated in vacuo. The crude residuewas dissolved in DCM (50 mL) and washed with H₂O (150 mL×2). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by reverse phase chromatography(acetonitrile 10-40%/0.225% formic acid in water) to give the titlecompound (120 mg). LCMS M/Z (M+H) 427.

Step 8:8-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-6-chloroisoquinolin-3-yltrifluoromethanesulfonate

To a solution of1-(3-(6-chloro-3-hydroxyisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(120 mg, 0.28 mmol) in DCM (3 mL) at 0° C. was added triethylamine (0.12mL, 0.84 mmol) and trifluoromethanesulfonic anhydride (0.06 mL, 0.37mmol). The reaction was stirred at room temperature for 16 h. DCM (30mL) was added and washed with water (30 mL×2). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givethe title compound (157 mg, crude) as a brown solid that required nofurther purification. LCMS M/Z (M+H) 559.

Step 9:1-(3-(6-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of8-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-6-chloroisoquinolin-3-yltrifluoromethanesulfonate (600 mg, crude) in 1,4-dioxane (10 mL) andwater (2 mL) was added[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (79 mg,0.11 mmol), Na₂CO₃ (341 mg, 3.21 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(223 mg, 1.07 mmol). The mixture was irradiated in a microwave at 60° C.for 0.5 h. EtOAc (50 mL) was added and washed with water (40 mL), brine(40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (acetonitrile 20-50%/0.05% NH₄OH in water) to give thetitle compound (10 mg) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.60(s, 1H), 8.13-7.93 (m, 2H), 7.79-7.73 (m, 2H), 7.43-7.40 (m, 1H),4.65-4.49 (m, 2H), 4.33-4.23 (m, 1H), 4.18-4.16 (m, 2H), 4.01-3.83 (m,2H), 4.00 (s, 3H), 3.60-3.54 (m, 2H), 2.93-2.86 (m, 2H), 2.44-2.41 (m,2H), 2.21-2.10 (m, 3H), 1.97-1.94 (m, 2H). LCMS M/Z (M+H) 491.

Example 311-(3-(6-ethyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1:1-(3-(3-(1-methyl-1H-pyrazol-4-yl)-6-vinylisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-(6-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Example 30, 110 mg, 0.22 mmol) in THF (3 mL) and water(0.6 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (10 mg, 0.02mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (16 mg, 0.02 mmol), Na₂CO₃ (71 mg, 0.67 mmol) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (345 mg, 2.24 mmol). Themixture was irradiated in a microwave at 60° C. for 0.5 h. EtOAc (50 mL)was added and extracted with water (40 mL), brine (40 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel chromatography(DCM/MeOH=10:1) to give the title compound (70 mg, 65%) as a brownsolid. LCMS M/Z (M+H) 483.

Step 2:1-(3-(6-ethyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-(3-(1-methyl-1H-pyrazol-4-yl)-6-vinylisoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(70 mg, 0.15 mmol) in MeOH (5 mL) was added 10% Pd/C (50 mg). Themixture was stirred at room temperature for 1 h under a hydrogenatmosphere (15 Psi). The mixture was filtered and the filtrate wasconcentrated in vacuo. The crude residue was purified by Prep-TLC(DCM/MeOH=10:1) to give the title compound (6 mg, 9%) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ 9.54-9.50 (m, 1H), 8.05-8.02 (m, 2H),7.78-7.75 (m, 1H), 7.60-7.56 (m, 1H), 7.36-7.34 (m, 1H), 4.66-4.43 (m,2H), 4.33-4.23 (m, 1H), 4.21-4.12 (m, 2H), 4.04-3.81 (m, 2H), 4.00 (s,3H), 3.60-3.54 (m, 2H), 2.94-2.81 (m, 4H), 2.53-2.38 (m, 2H), 2.22-2.05(m, 3H), 1.97-1.94 (m, 2H), 1.40-1.34 (m, 3H). LCMS M/Z (M+H) 485.

Example 328-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline-4-carbonitrile

Step 1: 2-chloro-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)benzaldehyde

a solution of 2-bromo-6-chlorobenzaldehyde (13 g, 59.2 mmol) intriethylamine (650 mL) was added bis(triphenylphosphine)palladium(II)dichloride (2.1 g, 3.0 mmol) and 4-ethynyl-1-methyl-1H-pyrazole (10.4 g,98 mmol) and copper(I) iodide (650 mg, 3.4 mmol). The mixture was heatedto 80° C. for 16 h under a nitrogen atmosphere. After cooling thereaction to room temperature, the mixture was filtered and concentratedin vacuo. The crude residue was purified by silica gel chromatography(petroleum ether/EtOAc=5:1) to give the title compound (6.9 g, 48%) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.52 (s, 1H), 7.58 (s, 1H),7.53 (s, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.35-7.24 (m, 2H), 3.82 (s, 3H).LCMS M/Z (M+H) 245.

Step 2: (2-chloro-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)methanol

To a solution of2-chloro-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)benzaldehyde (6.9 g, 28.2mmol) in MeOH (60 mL) at 0° C. was added sodium borohydride (1.7 g, 43.9mmol) portionwise. The mixture was stirred at room temperature for 2 hunder a nitrogen atmosphere. The reaction was concentrated in vacuo.Water (50 mL) was added and extracted with EtOAc (50 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (8.2 g, crude) as ayellow solid that required no further purification. ¹H NMR (400 MHz,CDCl₃) δ 7.65 (s, 1H), 7.58 (s, 1H), 7.41 (d, J=7.2 Hz, 1H), 7.34 (d,J=8.0 Hz, 1H), 7.23-7.19 (m, 1H), 5.01 (d, J=6.0 Hz, 2H), 3.90 (s, 3H),2.51 (t, J=6.4 Hz, 1H). LCMS M/Z (M+H) 247.

Step 3: 4-((2-(azidomethyl)-3-chlorophenyl)ethynyl)-1-methyl-1H-pyrazole

To a solution of(2-chloro-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)methanol (7.2 g,29 mmol) in toluene (80 mL) was added diphenylphosphoryl azide (9.6 g,34.8 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.7 g, 37.6 mmol).The mixture was stirred at room temperature for 16 h under a nitrogenatmosphere. DCM (30 mL) was added and washed with water (30 mL×2). Theorganic phase was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to give the title compound (9 g, crude) as yellow oil thatrequired no further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (s,1H), 7.74 (s, 1H), 7.62-7.52 (m, 1H), 7.46-7.38 (m, 1H), 7.28-7.10 (m,1H), 4.73 (s, 2H), 3.87 (s, 3H). LCMS M/Z (M+H) 272.

Step 4: 8-chloro-4-iodo-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline

To a solution of4-((2-(azidomethyl)-3-chlorophenyl)ethynyl)-1-methyl-1H-pyrazole (7.9 g,28.9 mmol) in DCM (500 mL) was added iodine (36.8 g, 144.9 mmol) andK₃PO₄ (30.8 g, 145 mmol). The mixture was stirred at room temperaturefor 24 h under a nitrogen atmosphere and washed with water (400 mL×2).The organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=1:1) to give the title compound(10 g, 94%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.43 (s, 1H),8.47 (s, 1H), 8.18-8.15 (m, 2H), 7.90-1.86 (m, 2H), 3.95 (s, 3H). LCMSM/Z (M+H) 370.

Step 5: 8-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline-4-carbonitrile

To a solution of 8-chloro-4-iodo-3-(1-methylpyrazol-4-yl)isoquinoline(500 mg, 1.35 mmol) in DMF (10 mL) was added copper(I) cyanide (133 mg,1.49 mmol) and tetrakis(triphenylphosphine)palladium(0) (156 mg, 0.14mmol). The mixture was heated to 120° C. for 16 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. DCM (50 mL) was added and washedwith water (40 mL) and brine (40 mL). The organic phase was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica gel chromatography (petroleum ether/EtOAc=1:1) togive the title compound (300 mg, 83%) as a brown solid. LCMS M/Z (M+H)269.

Step 6:3-(1-methyl-1H-pyrazol-4-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-4-carbonitrile

To a solution of8-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline-4-carbonitrile (300mg, 1.12 mmol) in 1,4-dioxane (5 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (52 mg, 0.11mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (87 mg, 0.11 mmol), KOAc (328 mg, 3.35 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (850 mg,3.35 mmol). The mixture was heated to 90° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.

Step 7:8-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline-4-carbonitrile

To the above reaction mixture was added1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 300 mg, 0.92 mmol),2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (38 mg, 0.08mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (63 mg, 0.08 mmol), Na₂CO₃ (266 mg, 2.5 mmol) and water (1mL). The mixture was heated to 60° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, DCM (50 mL)was added and washed with water (40 mL), brine (40 mL). The organicphase was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by reverse phase chromatography(acetonitrile 23-53%/0.2% formic acid in water) to give the titlecompound (11 mg, 3%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.90(d, J=6.0 Hz, 1H), 8.52-8.38 (m, 2H), 8.22-8.17 (m, 1H), 7.96-7.84 (m,1H), 7.66-7.54 (m, 1H), 4.68-4.51 (m, 2H), 4.32-4.27 (m, 1H), 4.19-4.16(m, 2H), 4.04 (s, 3H), 4.02-3.84 (m, 2H), 3.61-3.55 (m, 2H), 2.99-2.81(m, 2H), 2.48-2.39 (m, 2H), 2.27-2.06 (m, 3H), 1.98-1.95 (m, 2H). LCMSM/Z (M+H) 482.

Example 331-(3-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: 8-chloro-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline

To a solution of 8-chloro-4-iodo-3-(1-methylpyrazol-4-yl)isoquinoline(300 mg, 0.81 mmol) in DMF (15 mL) and water (3 mL) was added potassiummethyltrifluoroborate (495 mg, 4.1 mmol), butyl di-1-adamantylphosphine(30 mg, 0.08 mmol), palladium(II) acetate (18 mg, 0.08 mmol) and Cs₂CO₃(795 mg, 2.4 mmol). The mixture was heated to 80° C. for 20 h under anitrogen atmosphere. After cooling the reaction to room temperature,EtOAc (50 mL) was added and washed with water (40 mL×2) and brine (40mL). The organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=1:1) to give the title compound(200 mg, 95%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.57 (s, 1H),7.98 (d, J=8.0 Hz, 1H), 7.95-7.90 (m, 2H), 7.67-7.57 (m, 2H), 4.02 (s,3H), 2.79 (s, 3H). LCMS M/Z (M+H) 258.

Step 2:4-methyl-3-(1-methyl-1H-pyrazol-4-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline

To a solution of8-chloro-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline (200 mg, 0.78mmol) in 1,4-dioxane (5 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (38 mg, 0.08mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (64 mg, 0.08 mmol), KOAc (228 mg, 2.33 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (591 mg,2.33 mmol). The mixture was heated to 90° C. for 16 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. EtOAc (50 mL) was added andwashed with water (40 mL×2) and brine (40 mL). The organic phase wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (petroleumether/EtOAc=3:1) to give the title compound (100 mg, 37%) as a brownsolid. LCMS M/Z (M+H) 350.

Step 3:1-(3-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of4-methyl-3-(1-methyl-1H-pyrazol-4-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(100 mg, 0.29 mmol) in THF (3 mL) and water (0.6 mL) was added1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate H, 103 mg, 0.31 mmol),2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (14 mg, 0.03mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (24 mg, 0.03 mmol), Na₂CO₃ (91 mg, 0.86 mmol). The mixturewas heated to 60° C. for 16 h under a nitrogen atmosphere. After coolingthe reaction to room temperature, EtOAc (50 mL) was added and washedwith water (40 mL), brine (40 mL). The organic phase was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 20-50%/0.05%NH₄OH in water) to give the title compound (14 mg, 10%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 9.61-9.48 (m, 1H), 8.14-8.04 (m, 1H),7.95-7.90 (m, 2H), 7.84-7.74 (m, 1H), 7.61-7.50 (m, 1H), 4.63-4.44 (m,2H), 4.31-4.25 (m, 1H), 4.20-4.12 (m, 2H), 4.01 (s, 3H), 4.00-3.83 (m,2H), 3.59-3.54 (m, 2H), 2.96-2.82 (m, 2H), 2.81 (s, 3H), 2.48-2.39 (m,2H), 2.21-2.05 (m, 3H), 1.98-1.95 (m, 2H). LCMS M/Z (M+H) 471.

Example 34N-methyl-3-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

Step 1: tert-butyl3-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of4-methyl-3-(1-methyl-1H-pyrazol-4-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(300 mg, 0.86 mmol) in THF (10 mL) and water (2 mL) was added tert-butyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate G, 398 mg, 1.03 mmol),2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (43 mg, 0.09mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (71 mg, 0.09 mmol), Na₂CO₃ (273 mg, 2.58 mmol). Themixture was heated to 60° C. for 16 h under a nitrogen atmosphere. Aftercooling the reaction to room temperature, DCM (70 mL) was added andwashed with water (50 mL), brine (50 mL). The organic phase was driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (DCM/MeOH=50:1) togive the title compound (200 mg, 44%) as a brown solid. LCMS M/Z (M+H)529.

Step 2:4-methyl-3-(1-methyl-1H-pyrazol-4-yl)-8-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoquinoline

To a solution of tert-butyl3-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(200 mg, 0.38 mmol) in DCM (3 mL) at 0° C. was added trifluoroaceticacid (0.28 mL, 3.78 mmol). The mixture was stirred at room temperaturefor 12 h. DCM (20 mL) was added and washed with sat. aq. NaHCO₃ (10mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuoto give the title compound (180 mg, crude) as brown oil that required nofurther purification. LCMS M/Z (M+H) 429.

Step 3:N-methyl-3-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

To a solution of4-methyl-3-(1-methyl-1H-pyrazol-4-yl)-8-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoquinoline(180 mg, 0.42 mmol) in DCM (5 mL) was added triethylamine (0.23 mL, 1.68mmol) and N-methyl-1H-imidazole-1-carboxamide (105 mg, 0.84 mmol). Themixture was stirred at room temperature for 12 h. DCM (40 mL) was added,washed with water (40 mL×2) and brine (40 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile20-50%/0.05% NH₄OH in water) to give the title compound (53 mg, 24%) asa white solid. ¹H NMR (400 MHz, CDCl₃) 9.44 (s, 1H), 8.01 (d, J=8.4 Hz,1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.72-7.68 (m, 1H), 7.49 (d, J=7.2 Hz,1H), 4.85-4.72 (m, 1H), 4.35-4.21 (m, 3H), 4.13-4.10 (m, 2H), 3.96 (s,3H), 3.85-3.82 (m, 2H), 3.56-3.50 (m, 2H), 2.84-2.81 (m, 2H), 2.78-2.67(m, 6H), 2.48-2.32 (m, 2H), 1.96-1.87 (m, 2H). LCMS M/Z (M+H) 486.

Example 351-(3-(1-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: 8-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline

To a solution of 3-bromo-8-chloroisoquinoline (500 mg, 2.1 mmol) in1,4-dioxane (10 mL) and water (2 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (75 mg, 0.1mmol), Na₂CO₃ (437 mg, 4.1 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(472 mg, 2.3 mmol). The mixture was heated to 90° C. for 16 h under anitrogen atmosphere. After cooling the reaction to room temperature,EtOAc (30 mL) was added and washed with water (20 mL×2). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel chromatography(DCM/MeOH=20:1) to give the title compound (430 mg, 85%) as a yellowsolid. H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.37 (s, 1H), 8.14 (s,1H), 8.10 (s, 1H), 7.89-7.86 (m, 1H), 7.72-7.70 (m, 2H), 3.92 (s, 3H).

Step 2: 8-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline 2-oxide

To a solution of 8-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline (1.38g, 5.66 mmol) in DCM (100 mL) was added 3-chloroperoxybenzoic acid (3.45g, 16.99 mmol). The mixture was stirred at 16° C. for 3 h. DCM (200 mL)was added and washed with sat. aq. NaHCO₃ (100 mL×3). The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the titlecompound (600 mg, 41%) as a white solid.

Step 3: 8-chloro-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline

To a solution of 8-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline2-oxide (750 mg, 2.89 mmol), magnesium chloride (825 mg, 8.66 mmol) andcopper(I) chloride (14 mg, 0.15 mmol) in diethyl ether (50 mL) at 0° C.was added methylmagnesium bromide (3 M, 3.85 mL, 11.55 mmol). Themixture was stirred at room temperature for 16 h. Sat. aq. NH₄Cl (100mL) was added and extracted with DCM (50 mL×3). The combined organiclayers were washed with brine (50 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified byPrep-TLC (DCM/MeOH=50:1) to give the title compound (40 mg, 5%) as ayellow solid. LCMS M/Z (M+H) 258.

Step 4:1-(1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 200 mg, 0.61 mmol) in 1,4-dioxane (4 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (17 mg, 0.04mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (14 mg, 0.02 mmol), KOAc (179 mg, 1.83 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (309 mg,1.22 mmol). The mixture was heated to 80° C. for 3 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 376.

Step 5:1-(3-(1-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To the above step cooled solution was added8-chloro-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline (40 mg, 0.16mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (8 mg,0.02 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (6 mg, 0.01 mmol), K₃PO₄ (117 mg, 0.55 mmol), 1,4-dioxane(1 mL) and water (1 mL). The reaction mixture was heated to 90° C. for 2h under a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. Water (50 mL) was addedand extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine (30 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (acetonitrile 18-48%/0.05% NH₄OH in water) to give thetitle compound (1 mg, 1%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.03-8.00 (m, 2H), 7.84-7.82 (m, 1H), 7.69-7.61 (m, 2H), 7.42-7.40 (m,1H), 4.45-4.35 (m, 1H), 4.26-4.22 (m, 2H), 4.15-4.12 (m, 2H), 4.00-3.75(m, 2H), 3.97 (s, 3H), 3.58-3.52 (m, 2H), 2.93-2.86 (m, 2H), 2.39-2.36(m, 5H), 2.21-2.04 (m, 3H), 1.94-1.91 (m, 2H). LCMS M/Z (M+H) 471.

Example 36(S)-1-(3-(6-(1-methyl-1H-pyrazol-4-yl)naphthalen-1-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: 6-(1-methyl-1H-pyrazol-4-yl)naphthalen-1-amine

To a solution of 6-bromonaphthalen-1-amine (470 mg, 2.12 mmol) in1,4-dioxane (25 mL) and water (5 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (155 mg,0.21 mmol), Na₂CO₃ (449 mg, 4.24 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(528 mg, 2.54 mmol). The mixture was heated to 120° C. for 3 h under anitrogen atmosphere. After cooling the reaction to room temperature,water (100 mL) was added and extracted with EtOAc (50 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=30:1) to give the title compound (300 mg, 63%)as yellow solid. LCMS M/Z (M+H) 224.

Step 2: 4-(5-bromonaphthalen-2-yl)-1-methyl-1H-pyrazole

To a solution of 6-(1-methyl-1H-pyrazol-4-yl)naphthalen-1-amine (150 mg,0.67 mmol) in HCl (2.0 M, 6 mL) at 0° C. was added sodium nitrite (51mg, 0.74 mmol) in water (4 mL) slowly. The mixture was stirred at 0° C.for 1 h. Copper (I) bromide (350 mg, 2.44 mmol) in water (5 mL) at 0° C.was added by dropwise. The mixture was stirred at 0° C. for anadditional 1 h. Water (50 mL) was added and extracted with EtOAc (30mL×3). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified byPrep-TLC (DCM/MeOH=20:1) to give the title compound (40 mg, 17%) as ayellow solid. LCMS M/Z (M+H) 287.

Step 3:1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-pyrazole

To a solution of 4-(5-bromonaphthalen-2-yl)-1-methyl-1H-pyrazole (40 mg,0.14 mmol), KOAc (27 mg, 0.28 mmol) and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(70 mg, 0.28 mmol) in 1,4-dioxane (10 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.01mmol). The mixture was heated to 80° C. for 16 h under a nitrogenatmosphere. After cooling the reaction to room temperature, water (30mL) was added and extracted with EtOAc (20 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by Prep-TLC (petroleumether/EtOAc=3:1) to give the title compound (30 mg, 64%) as a yellowsolid.

Step 4:(S)-1-(3-(6-(1-methyl-1H-pyrazol-4-yl)naphthalen-1-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of(S)-1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate E, 28 mg, 0.09 mmol) in THF (5 mL) and water (1 mL) wasadded1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-pyrazole(30 mg, 0.09 mmol),2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (4 mg, 0.01mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (7 mg, 0.01 mmol), Na₂CO₃ (19 mg, 0.18 mmol). The mixturewas heated to 60° C. for 16 h under a nitrogen atmosphere. After coolingthe reaction to room temperature, water (50 mL) was added and extractedwith EtOAc (30 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 23-53%/0.05%NH₄OH in water) to give the title compounds (4 mg, 11%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 8.16-8.14 (m, 1H), 7.98-7.85 (m, 3H),7.76-7.74 (m, 1H), 7.66-7.57 (m, 1H), 7.55-7.47 (m, 1H), 7.45-7.40 (m,1H), 4.93-4.91 (m, 1H), 4.56-4.39 (m, 2H), 4.23-4.18 (m, 2H), 4.16-4.01(m, 2H), 4.00 (s, 3H), 3.99-3.82 (m, 2H), 2.91-2.85 (m, 2H), 2.61-2.43(m, 2H), 2.20-2.04 (m, 3H). LCMS M/Z (M+H) 442.

Example 37N-methyl-3-(2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

Step 1: 5-chloro-1,2-dihydroisoquinolin-3(4H)-one

A mixture of 2-(2-chlorophenyl)acetonitrile (5 g, 32.98 mmol),paraformaldehyde (1.09 g, 36.28 mmol) and pyrophosphoric acid (29.35 g,164.92 mmol) was heated to 180° C. for 15 min. The reaction mixture waspoured into ice water (200 mL), neutralized with Na₂CO₃, and thenextracted with DCM (100 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (DCM/MeOH=20:1) togive the title compound (400 mg, 7%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 7.35 (d, J=8.0 Hz, 1H), 7.24-7.18 (m, 1H), 7.09 (d, J=8.0 Hz,1H), 4.57 (s, 2H), 3.70 (s, 2H). LCMS M/Z (M+H) 182.

Step 2:5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1,2-dihydroisoquinolin-3(4H)-one

To a solution of 5-chloro-1,2-dihydroisoquinolin-3(4H)-one (500 mg, 2.75mmol) in 1,4-dioxane (10 mL) was added copper(I) iodide (26 mg, 0.14mmol), (1R,2R)-cyclohexane-1,2-diamine (63 mg, 0.55 mmol), K₃PO₄ (1.75g, 8.26 mmol) and 4-iodo-1-methyl-1H-pyrazole (859 mg, 4.13 mmol). Thereaction mixture was heated to 120° C. for 12 h under a nitrogenatmosphere. After cooling to room temperature, the mixture was filteredand concentrated in vacuo. Water (100 mL) was added and extracted withEtOAc (50 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (DCM/MeOH=20:1) to give the titlecompound (80 mg, 11%) as a yellow solid. LCMS M/Z (M+H) 262.

Step 3: tert-butyl1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate G, 400 mg, 1.04 mmol) in 1,4-dioxane (8 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (30 mg, 0.06mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (25 mg, 0.03 mmol), KOAc (300 mg, 3.12 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (526 mg,2.08 mmol). The mixture was heated to 80° C. for 2 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 434.

Step 4: tert-butyl3-(2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To the above step cooled solution was added5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1,2-dihydroisoquinolin-3(4H)-one(100 mg, 0.38 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (25 mg, 0.03 mmol), K₃PO₄ (244 mg, 1.15 mmol), 1,4-dioxane(2 mL) and water (2 mL). The reaction mixture was heated to 90° C. for 1h under a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. Water (100 mL) was addedand extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine (50 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=20:1) to give the title compound (60 mg, 12%)as a yellow solid. LCMS M/Z (M+H) 533.

Step 5:2-(1-methyl-1H-pyrazol-4-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2-dihydroisoquinolin-3(4H)-one

To a solution of tert-butyl3-(2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(60 mg, 0.11 mmol) in DCM (10 mL) at 0° C. was added trifluoroaceticacid (3 mL, 40 mmol). The mixture was stirred at 0° C. for 2 h andconcentrated in vacuo to give the title compound (50 mg, crude) as brownoil that required no further purification. LCMS M/Z (M+H) 433.

Step 6:N-methyl-3-(2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

To a solution of2-(1-methyl-1H-pyrazol-4-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2-dihydroisoquinolin-3(4H)-one(50 mg, 0.12 mmol) in DCM (15 mL) was added triethylamine (0.10 mL, 0.70mmol) and N-methyl-1H-imidazole-1-carboxamide (43 mg, 0.35 mmol). Thereaction was stirred at room temperature for 16 h. DCM (40 mL) was addedand washed with brine (30 mL×3). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 23-53%/0.2%formic acid in water) to give the title compound (14 mg, 24%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 2H), 7.58 (s, 1H), 7.35-7.27(m, 3H), 4.88 (s, 2H), 4.87-4.80 (m, 1H), 4.26 (s, 2H), 4.25-4.17 (m,1H), 4.16-4.10 (m, 2H), 3.91 (s, 3H), 3.87-3.80 (m, 4H), 3.55 (t, J=11.6Hz, 2H), 2.85-2.77 (m, 5H), 2.40-2.29 (m, 2H), 1.95-1.87 (m, 2H). LCMSM/Z (M+H) 490.

Example 38N-methyl-3-(3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

Step 1: N-(1-(2-chlorophenyl)propan-2-yl)-1-methyl-1H-pyrazol-4-amine

To a solution of 1-(2-chlorophenyl)propan-2-one (4.0 g, 23.7 mmol) inMeOH (50 mL) was added 1-methyl-1H-pyrazol-4-amine (3.49 g, 26.09 mmol)and NaHCO₃ (3.99 g, 47.44 mmol). The reaction mixture was heated to 50°C. for 2 h under a nitrogen atmosphere. After cooling to 0° C., sodiumborohydride (916 mg, 24.22 mmol) was added portionwise. The mixture wasstirred at room temperature for 2 h under a nitrogen atmosphere. Thereaction was concentrated in vacuo. Water (100 mL) was added andextracted with EtOAc (50 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (DCM/MeOH=20:1) togive the title compound (2.2 g, 55%) as brown oil. ¹H NMR (400 MHz,CDCl₃) δ 7.38-7.35 (m, 1H), 7.25-7.15 (m, 3H), 7.14 (s, 1H), 6.95 (s,1H), 3.81 (s, 3H), 3.51-3.41 (m, 1H), 3.14-3.07 (m, 1H), 2.77-2.69 (m,1H), 1.16 (d, J=6.4 Hz, 3H). LCMS M/Z (M+H) 250.

Step 2:5-chloro-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline

To a solution ofN-(1-(2-chlorophenyl)propan-2-yl)-1-methyl-1H-pyrazol-4-amine (1.0 g, 4mmol) in AcOH (1 mL) was added paraformaldehyde (240 mg, 8.01 mmol). Themixture was stirred at room temperature for 5 min under a nitrogenatmosphere. After cooling to 0° C., H₂SO₄ (3.2 mL 1) was added. Themixture was stirred at room temperature for 16 h under a nitrogenatmosphere. The reaction mixture was poured into water (100 mL),basified with solid NaHCO₃ to pH 8 and then extracted with EtOAc (50mL×3). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified bysilica gel chromatography (DCM/MeOH=20:1) to give the title compound(300 mg, 29%) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.25-7.09 (m,4H), 7.05-6.97 (m, 1H), 4.22-4.02 (m, 2H), 3.85-3.81 (m, 3H), 3.76-3.66(m, 1H), 3.08-3.00 (m, 1H), 2.78-2.72 (m, 1H), 1.08 (d, J=6.4 Hz, 3H).LCMS M/Z (M+H) 262.

Step 3: tert-butyl1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate G, 1.0 g, 2.59 mmol) in 1,4-dioxane (20 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (74 mg, 0.16mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (61 mg, 0.08 mmol), KOAc (762 mg, 7.77 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.32 g,5.18 mmol). The mixture was heated to 80° C. for 5 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 434.

Step 4: tert-butyl3-(3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To the above step cooled solution was added5-chloro-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline(300 mg, 1.15 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (57 mg, 0.07 mmol), K₃PO₄ (612 mg, 2.88 mmol), 1,4-dioxane(4 mL) and water (6 mL). The reaction mixture was heated to 90° C. for 1h under a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. Water (50 mL) was addedand extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine (30 mL×3), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=20:1) to give the title compound (70 mg, 11%)as a yellow solid. LCMS M/Z (M+H) 533.

Step 5:3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline

To a solution of tert-butyl3-(3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(70 mg, 0.12 mmol) in DCM (10 mL) at 0° C. was added trifluoroaceticacid (0.11 mL, 1.2 mmol). The mixture was stirred at 0° C. for 2 h andconcentrated in vacuo to give the title compound (50 mg, crude) as brownoil that required no further purification. LCMS M/Z (M+H) 433.

Step 6:N-methyl-3-(3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

To a solution of3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline(50 mg, 0.12 mmol) in DCM (10 mL) was added triethylamine (0.10 mL, 0.70mmol) and N-methyl-1H-imidazole-1-carboxamide (43 mg, 0.35 mmol). Thereaction was stirred at room temperature for 16 h. DCM (40 mL) was addedand washed with brine (30 mL×3). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 23-53%/0.2%formic acid in water) to give the title compound (2 mg, 3%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.08 (m, 4H), 7.02 (s, 1H),4.48-4.39 (m, 1H), 4.30-4.07 (m, 7H), 3.97-3.88 (m, 1H), 3.86 (s, 3H),3.80-3.65 (m, 3H), 3.55 (t, J=11.6 Hz, 2H), 3.20-3.12 (m, 1H), 2.80 (d,J=4.4 Hz, 3H), 2.75-2.62 (m, 1H), 2.39-2.29 (m, 2H), 1.95-1.86 (m, 2H),1.03 (d, J=6.4 Hz, 3H). LCMS M/Z (M+H) 490.

Example 39N-methyl-3-(2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

Step 1:5-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline

o a solution of 5-bromo-1,2,3,4-tetrahydroisoquinoline (1.0 g, 4.72mmol) in ethylene glycol (15 mL) was added copper(I) iodide (898 mg,4.72 mmol), K₃PO₄ (3.0 g, 14.15 mmol) and 4-iodo-1-methyl-1H-pyrazole(1.96 g, 9.43 mmol). The reaction mixture was heated to 120° C. for 3 hunder a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. Water (50 mL) was addedand extracted with DCM (30 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (petroleumether/EtOAc=1:1) to give the title compound (0.28 g, 42% purity) as abrown solid which was further purified by reverse phase chromatography(acetonitrile 5-35/0.05% HCl in water) to give the title compound (0.05g, 4%, HCl salt) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ9.77 (s, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.99(d, J=7.2 Hz, 1H), 7.60-7.54 (m, 1H), 4.55 (t, J=8.0 Hz, 2H), 3.95 (s,3H), 3.38 (t, J=8.0 Hz, 2H), 2.54 (s, 2H). LCMS M/Z (M+H) 292.

Step 2: tert-butyl1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate G, 100 mg, 0.26 mmol) in 1,4-dioxane (4 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (14 mg, 0.03mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (24 mg, 0.03 mmol), KOAc (76 mg, 0.78 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (131 mg,0.52 mmol). The mixture was heated to 80° C. for 2 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 434.

Step 3: tert-butyl3-(2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To the above step cooled solution was added5-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline (25mg, 0.09 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl(5 mg, 0.01 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (8 mg, 0.01 mmol), K₃PO₄ (59 mg, 0.28 mmol), 1,4-dioxane(1 mL) and water (1 mL). The reaction mixture was heated to 90° C. for 1h under a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. DCM (50 mL) was addedand washed with water (40 mL), brine (40 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (DCM/MeOH=20:1)to give the title compound (50 mg, 52%) as brown oil. LCMS M/Z (M+H)519.

Step 4:2-(1-methyl-1H-pyrazol-4-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline

To a solution of tert-butyl3-(2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(50 mg, 0.1 mmol) in DCM (1 mL) at 0° C. was added trifluoroacetic acid(0.07 mL, 0.96 mmol). The mixture was stirred at room temperature for 1h and concentrated in vacuo to give the title compound (43 mg, crude) asbrown oil that required no further purification. LCMS M/Z (M+H) 419.

Step 5:N-methyl-3-(2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

To a solution of2-(1-methyl-1H-pyrazol-4-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline(43 mg, 0.10 mmol) in DCM (3 mL) was added triethylamine (0.07 mL, 0.5mmol) and N-methyl-1H-imidazole-1-carboxamide (25 mg, 0.2 mmol). Thereaction was stirred at room temperature for 12 h. DCM (50 mL) was addedand washed with water (40 mL), brine (40 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile15-45%/0.05% NH₄OH in water) to give the title compound (7 mg, 14%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.30 (s, 1H), 7.22 (d, J=7.6 Hz,1H), 7.17-7.11 (m, 2H), 7.04 (s, 1H), 4.46-4.37 (m, 1H), 4.25-4.09 (m,6H), 3.90-3.80 (m, 4H), 3.58-3.45 (m, 4H), 3.26-3.21 (m, 2H), 3.04-3.01(m, 2H), 2.85-2.77 (m, 4H), 2.41-2.25 (m, 2H), 1.91-1.87 (m, 2H). LCMSM/Z (M+H) 476.

Example 40N-methyl-3-(2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

Step 1: tert-butyl3-(2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate G, 1.0 g, 2.59 mmol) in toluene (20 mL) was addedcopper(I) iodide (25 mg, 0.13 mmol), K₃PO₄ (2.2 g, 10.36 mmol),(1R,2R)-cyclohexane-1,2-diamine (59 mg, 0.52 mmol) and2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridine (500 mg,2.36 mmol). The mixture was heated to 120° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. Water (100 mL) was added andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=20:1) to give the title compound (90 mg, 7%) asa yellow solid. LCMS M/Z (M+H) 518.

Step 2:3-(2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of tert-butyl3-(2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(90 mg, 0.17 mmol) in DCM (10 mL) at 0° C. was added trifluoroaceticacid (0.06 mL, 0.87 mmol). The mixture was stirred at 0° C. for 2 h andconcentrated in vacuo to give the title compound (60 mg, crude) as ayellow solid that required no further purification. LCMS M/Z (M+H) 418.

Step 3:N-methyl-3-(2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-H-pyrazol-4-yl)-H-pyrrolo[2,3-c]pyridin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

To a solution of3-(2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(60 mg, 0.14 mmol) in DCM (10 mL) at 0° C. was added triethylamine (0.04mL, 0.29 mmol) and N-methyl-1H-imidazole-1-carboxamide (36 mg, 0.29mmol). The reaction was stirred at room temperature for 16 h. DCM (40mL) was added and washed with brine (30 mL×3). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile28-58%/0.2% formic acid in water) to give the title compound (9 mg, 13%)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1H), 8.08 (s, 1H),7.95 (s, 1H), 7.68 (s, 1H), 6.46 (s, 1H), 5.10-5.02 (m, 1H), 4.31-4.18(m, 1H), 4.16-4.11 (m, 4H), 3.97 (s, 3H), 3.86 (t, J=5.6 Hz, 2H), 3.56(t, J=11.6 Hz, 2H), 2.91-2.80 (m, 2H), 2.77 (d, J=3.6 Hz, 3H), 2.42 (s,3H), 2.36-2.25 (m, 2H), 1.98-1.87 (m, 2H). LCMS M/Z (M+H) 475.

Example 411-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-indole-6-carbonitrile

Step 1: 5-bromo-6-chloro-1-(phenylsulfonyl)-1H-indole

To a stirred solution of 5-bromo-6-chloro-1H-indole (5.0 g, 21.69 mmol)in DMF (50 mL) at 0° C. was added NaH (60%, 1.3 g, 32.54 mmol) and themixture was stirred at room temperature for 30 min. Benzenesulfonylchloride (3.33 mL, 26.03 mmol) was added dropwise and the mixturestirred for an additional 2 h. The mixture was quenched with sat. aq.NH₄Cl (100 mL) and extracted with EtOAc (100 mL×3). The combined organiclayers were washed with brine (50 mL×3), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was recrystallizedwith DCM (20 mL) and TBME (200 mL) to give the title compound (6.0 g,75%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H),7.98-7.93 (m, 2H), 7.90 (s, 1H), 7.74 (d, J=4.0 Hz, 1H), 7.69-7.63 (m,1H), 7.60-7.51 (m, 2H), 6.73 (d, J=4.0 Hz, 1H).

Step 2: 5-bromo-6-chloro-2-methyl-1-(phenylsulfonyl)-1H-indole

To a solution of 5-bromo-6-chloro-1-(phenylsulfonyl)-1H-indole (1.0 g,2.56 mmol) in THF (10 mL) was added LDA (1.92 mL, 3.84 mmol, 2 M inTHF). The reaction was stirred at −78° C. for 2 h under a nitrogenatmosphere. Iodomethane (0.24 mL, 3.84 mmol) was added drop wise, thecooling bath was removed and the mixture was stirred at room temperaturefor 1 h. The mixture was quenched with sat. aq. NH₄Cl (20 mL) andextracted with EtOAc (100 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give thetitle compound (0.8 g, crude) as a yellow solid that required no furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H), 7.81-7.75 (m, 2H),7.65 (s, 1H), 7.64-7.57 (m, 1H), 7.54-7.46 (m, 2H), 6.27 (s, 1H), 2.57(s, 3H).

Step 3:6-chloro-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-indole

To a solution of 5-bromo-6-chloro-2-methyl-1-(phenylsulfonyl)-1H-indole(11.76 g, 26 mmol) in 1,4-dioxane (100 mL) and water (25 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.9 g, 2.6mmol), Na₂CO₃ (5.51 g, 51.99 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(6.49 g, 31.19 mmol). The mixture was heated to 90° C. for 12 h under anitrogen atmosphere. After cooling the reaction to room temperature,water (200 mL) was added and extracted with EtOAc (200 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=2:1) to give the title compound(4.6 g, 46%) as a yellow solid. LCMS M/Z (M+H) 386.

Step 4: 6-chloro-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-indole

To a solution of6-chloro-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-indole(1.8 g, 4.66 mmol) in THF (30 mL) was added TBAF (9.33 ml, 9.33 mmol, 1M in THF). The mixture was heated to 65° C. for 2 h under a nitrogenatmosphere. The reaction mixture was concentrated in vacuo. The cruderesidue was dissolved in EtOAc (100 mL) and washed with water (100mL×3). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=6:1) to give the title compound(1.1 g, 86%) as a yellow solid. LCMS M/Z (M+H) 246.

Step 5:1-(3-(6-chloro-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-indol-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 1.1 g, 3.35 mmol) in toluene (8 mL) was added copper(I)iodide (32 mg, 0.17 mmol), K₃PO₄ (2.85 g, 13.41 mmol),(1R,2R)-cyclohexane-1,2-diamine (77 mg, 0.67 mmol) and6-chloro-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-indole (906 mg, 3.69mmol). The mixture was heated to 120° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. The crude residue was dissolvedin EtOAc (100 mL) and washed with water (100 mL×3). The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (DCM/MeOH=100:1)to give the title compound (1.0 g, 55%) as a yellow solid. LCMS M/Z(M+H) 493.

Step 6:1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-indole-6-carbonitrile

To a solution of1-(3-(6-chloro-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-indol-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (154 mg, 0.31 mmol) in 1,4-dioxane (1.5 mL) and water(1.5 mL) was added potassium hexacyanoferrate(II) trihydrate (92 mg,0.16 mmol), KOAc (4 mg, 0.04 mmol),methanesulfonato(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(25 mg, 0.03 mmol) and2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (13 mg, 0.03mmol). The mixture was heated to 120° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. The crude residue was purifiedby reverse phase chromatography (acetonitrile 18-48%/0.2% formic acid inwater) to give the title compound (15 mg, 10%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 8.13 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.53-7.43(m, 1H), 6.58 (s, 1H), 4.51-4.42 (m, 1H), 4.28-4.18 (m, 2H), 4.02-3.96(m, 2H), 3.91 (s, 3H), 3.87-3.78 (m, 2H), 3.56-3.45 (m, 2H), 3.03-2.87(m, 2H), 2.34-2.30 (m, 3H), 2.10-1.87 (m, 7H). LCMS M/Z (M+H) 484.

Example 421-(3-(6-(difluoromethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-indol-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1:2,2-difluoro-2-(2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-indol-6-yl)-1-phenylethanone

To a solution of6-chloro-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-indole(4.0 g, 9.85 mmol) in toluene (40 mL) was added2,2-difluoro-1-phenyl-ethanone (3.08 g, 19.7 mmol),chloro[(tricyclohexylphosphine)-2-(2′-aminobiphenyl)]palladium(II) (505mg, 0.98 mmol) and K₃PO₄ (8.36 g, 39.39 mmol). The reaction mixture washeated to 120° C. for 16 h under a nitrogen atmosphere. After coolingthe reaction to room temperature, water (100 mL) was added and extractedwith DCM (100 mL×2). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (3 g, crude) as a yellow solid that required no furtherpurification. LCMS M/Z (M+H) 506.

Step 2:6-(difluoromethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-indole

To a solution of2,2-difluoro-2-(2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-indol-6-yl)-1-phenylethanone(0.5 g, 0.30 mmol) in toluene (5 mL) and water (0.08 mL) was added KOH(50 mg, 0.89 mmol). The reaction mixture was heated to 100° C. for 6 h.After cooling the reaction to room temperature, EtOAc (100 mL) was addedand washed with water (50 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (petroleumether/EtOAc=2/1) to give the title compound (0.2 g, 50%) as a yellowsolid. LCMS M/Z (M+H) 402.

Step 3:6-(difluoromethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-indole

To a solution of6-(difluoromethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-indole(400 mg, 1.0 mmol) in THF (4 mL) was added TBAF (2.0 ml, 2.0 mmol, 1 Min THF). The mixture was heated to 65° C. for 8 h under a nitrogenatmosphere. The reaction mixture was concentrated in vacuo. The cruderesidue was dissolved in EtOAc (100 mL) and washed with water (100mL×3). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=2:1) to give the title compound(150 mg, 58%) as a yellow solid. LCMS M/Z (M+H) 262.

Step 4:1-(3-(6-(difluoromethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-indol-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 130 mg, 0.40 mmol) in toluene (2 mL) was addedcopper(I) iodide (4 mg, 0.02 mmol), K₃PO₄ (336 mg, 1.58 mmol),(1R,2R)-cyclohexane-1,2-diamine (9 mg, 0.08 mmol) and6-(difluoromethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-indole (114mg, 0.44 mmol). The mixture was heated to 120° C. for 12 h under anitrogen atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by reverse phase chromatography (acetonitrile 25-55%/0.2%formic acid in water) to give the title compound (31 mg, 15%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (s, 1H), 7.58 (s, 1H), 7.57 (s,1H), 7.30-7.26 (m, 1H), 6.96 (t, J=55.2 Hz, 1H), 6.51 (s, 1H), 4.51-4.42(m, 1H), 4.25-4.18 (m, 2H), 4.02-3.96 (m, 2H), 3.90 (s, 3H), 3.87-3.78(m, 2H), 3.56-3.45 (m, 2H), 3.03-2.87 (m, 2H), 2.34-2.30 (m, 3H),2.10-1.95 (m, 7H). LCMS M/Z (M+H) 509.

Example 431-(1-methyl-3-(4-(1-methyl-1H-pyrazol-4-yl)benzoyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: methyl 4-(1-methyl-1H-pyrazol-4-yl)benzoate

To a solution of methyl 4-bromobenzoate (10 g, 46.5 mmol) in 1,4-dioxane(75 mL) and water (25 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.4 g, 4.65mmol), Na₂CO₃ (14.8 g, 139.5 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(14.5 g, 69.8 mmol). The mixture was heated to 120° C. for 12 h under anitrogen atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=5:1) togive the title compound (4.6 g, 46%) as yellow oil.

Step 2: 4-(1-methyl-1H-pyrazol-4-yl)benzoic acid

To a solution of methyl 4-(1-methyl-1H-pyrazol-4-yl)benzoate (4.6 g,21.3 mmol) in MeOH (50 mL) was added sodium hydroxide (5M, 42.6 mL). Themixture was heated to 50° C. for 5 h. After cooling the reaction to roomtemperature, the mixture was washed with EtOAc (100 mL). The aqueouslayer was acidified with HCl (2 N) to pH 2-3 and then extracted withEtOAc (100 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound(3.5 g, crude) as a white solid that required no further purification.

Step 3: N-methoxy-N-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzamide

To a solution of 4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (3.5 g, 17.3mmol) in DCM (100 mL) was added N,O-dimethylhydroxylamine hydrochloride(2.0 g, 20.8 mmol),(dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methaniminiumhexafluorophosphate (7.9 g, 20.8 mmol) and N,N-diisopropylethylamine(8.58 mL, 51.9 mmol). The mixture was stirred at room temperature for 8h. The reaction mixture was washed with 1 N HCl (100 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica gel chromatography (petroleum ether/EtOAc=3:1) togive the title compound (3.2 g, 75%) as a yellow solid.

Step 4: tert-butyl1-methyl-3-(4-(1-methyl-1H-pyrazol-4-yl)benzoyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(300 mg, 0.95 mmol) in THF (6 mL) at −78° C. was slowly added n-BuLi(2.5 M, 0.46 mL, 1.14 mmol) under a nitrogen atmosphere. After stirredat −78° C. for 30 min, the mixture was added a solution ofN-methoxy-N-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzamide (279 mg, 1.14mmol) in THF (0.5 mL) by dropwise. The mixture was stirred at −78° C.for an additional 2 h. The reaction mixture was quenched with water (20mL) and extracted with EtOAc (20 mL×2). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile45-75%/0.2% formic acid in water) to give the title compound (50 mg,13%) as a white solid.

Step 5:(4-(1-methyl-1H-pyrazol-4-yl)phenyl)(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone

A mixture of tert-butyl1-methyl-3-(4-(1-methyl-1H-pyrazol-4-yl)benzoyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(50 mg, 0.12 mmol) and trifluoroacetic acid (2 mL) in DCM (2 mL) wasstirred at room temperature for 3 h. The mixture was concentrated invacuo to give the title compound (30 mg, crude) as brown oil thatrequired no further purification.

Step 6:1-(1-methyl-3-(4-(1-methyl-1H-pyrazol-4-yl)benzoyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of(4-(1-methyl-1H-pyrazol-4-yl)phenyl)(1-methyl-4,5,6-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone(30 mg, 0.09 mmol) in DCM (1 mL) was added triethylamine (0.026 mL, 0.19mmol) and acetic anhydride (0.018 mL, 0.19 mmol). The mixture wasstirred at room temperature for 2 h. DCM (5 mL) was added and washedwith water (5 mL×2). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified byreverse phase chromatography (acetonitrile 32-62%/0.2% formic acid inwater) to give the title compound (6 mg, 18%) as a white solid. ¹H NMR(400 MHz, CD₃OD) δ 8.33-8.28 (m, 2H), 8.11 (s, 1H), 7.94 (s, 1H),7.71-7.68 (m, 2H), 4.82 (s, 2H), 3.96 (s, 3H), 3.95-3.84 (m, 2H), 4.90(s, 3H), 3.91-3.74 (m, 2H), 2.23-2.21 (m, 3H). LCMS M/Z (M+H) 364.

Example 44(S)-1-(3-(6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydronaphthalen-1-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: 6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydronaphthalen-1(2H)-one

To a solution of 6-bromo-3,4-dihydronaphthalen-1(2H)-one (0.9 g, 4.0mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (146 mg,0.20 mmol), K₂CO₃ (1.38 mg, 10.0 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(915 mg, 4.4 mmol). The mixture was heated to 120° C. for 16 h under anitrogen atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=5:1) togive the title compound (800 mg, 88%) as yellow oil. LCMS M/Z (M+H) 227.

Step 2:4-methyl-N′-(6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydronaphthalen-1(2H)-ylidene)benzenesulfonohydrazide

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydronaphthalen-1(2H)-one (0.8 g,3.54 mmol) in MeOH (10 mL) was added 4-methylbenzenesulfonohydrazide(725 mg, 3.89 mmol). The mixture was heated to 70° C. for 3 h under anitrogen atmosphere. After cooling the reaction to room temperature, themixture was filtered to give the title compound (1.2 g, 86%) as a whitesolid.

Step 3:(S)-1-(3-(6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydronaphthalen-1-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

To a solution of(S)-1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate E, 670 mg, 2.13 mmol) in 1,4-dioxane (5 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (65 mg, 0.09mmol), t-BuOLi (312 mg, 3.9 mmol) and4-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydronaphthalen-1(2H)-ylidene)benzenesulfonohydrazide(0.7 g, 1.77 mmol). The mixture was heated to 100° C. for 3 h under anitrogen atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (DCM/MeOH=20:1) to give the titlecompound (680 mg, 86%) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ7.70-7.68 (m, 1H), 7.55-7.53 (m, 1H), 7.23-7.10 (m, 3H), 6.13-6.10 (m,1H), 4.77-4.74 (m, 1H), 4.38-4.20 (m, 2H), 4.11-4.06 (m, 2H), 4.00-3.66(m, 4H), 3.87 (s, 3H), 2.82-2.71 (m, 4H), 2.40-2.29 (m, 4H), 2.11-1.99(m, 3H). LCMS M/Z (M+H) 444.

Example 45N-methyl-3-(3-(2-methylthiazol-5-yl)isoquinolin-8-yl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

Step 1: tetrahydro-2H-thiopyran-4-yl methanesulfonate

To a solution of tetrahydro-2H-thiopyran-4-ol (10 g, 84.6 mmol) andtriethylamine (35.4 mL, 253.8 mmol) in DCM (150 mL) at 0° C. was addedmethanesulfonyl chloride (10.7 mL, 138.8 mmol) dropwise under a nitrogenatmosphere. The mixture was stirred at 25° C. for 16 h. Water (100 mL)was added and extracted with DCM (100 mL×2). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo togive the title compound (17 g, crude) as yellow oil that required nofurther purification. ¹H NMR (400 MHz, DMSO-d₆) δ 4.73-4.69 (m, 1H),3.19 (s, 3H), 2.76-2.63 (m, 4H), 2.17-2.16 (m, 2H), 1.87-1.84 (m, 2H).

Step 2: tert-butyl3-bromo-1-(tetrahydro-2H-thiopyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate A, 10 g, 33.1 mmol) in DMF (50 mL) was added Cs₂CO₃ (27 g,82.7 mmol) and tetrahydro-2H-thiopyran-4-yl methanesulfonate (8.4 g,43.0 mmol). The mixture was heated to 80° C. for 16 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered. The mixture was diluted with EtOAc (100 mL) and washedwith brine (100 mL×2). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether:tert-butyl methylether:THF=from 10:1:1 to 3:1:1) to give the title compound (5.9 g, 44%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 4.17 (s, 2H), 4.09-4.04(m, 1H), 3.62-3.59 (m, 2H), 2.83-2.77 (m, 2H), 2.71-2.68 (m, 4H),2.13-2.10 (m, 2H), 2.03-1.93 (m, 2H), 1.44 (s, 9H).

Step 3: tert-butyl3-bromo-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-1-(tetrahydro-2H-thiopyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(500 mg, 1.24 mmol) in THF (4 mL) and water (1 mL) at 0° C. was addedOxone (382 mg, 0.62 mmol) portionwise. The mixture was stirred at 25° C.for 1 h. The reaction was quenched by sat. aq. Na₂SO₃ (5 mL) andextracted with DCM (5 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (511 mg, crude) as a white solid that required no furtherpurification. LCMS M/Z (M+H) 418.

Step 4: 5-(8-chloroisoquinolin-3-yl)-2-methylthiazole

To a solution of 8-chloroisoquinolin-3-yl trifluoromethanesulfonate (3.0g, 9.6 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.7 g,0.96 mmol), Na₂CO₃ (3.1 g, 28.9 mmol) and2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (2.2 g,9.6 mmol). The mixture was heated to 90° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, DCM (80 mL)was added and washed with water (50 mL×2), brine (30 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel chromatography(petroleum ether/EtOAc=2:1) to give the title compound (0.8 g, 32%) as ayellow solid. LCMS M/Z (M+H) 261.

Step 5:2-methyl-5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)thiazole

To a solution of 5-(8-chloroisoquinolin-3-yl)-2-methylthiazole (300 mg,1.1 mmol) in 1,4-dioxane (4 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (55 mg, 0.1mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (90 mg, 0.1 mmol), KOAc (282 mg, 2.9 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (876 mg, 3.5mmol). The mixture was heated to 90° C. for 1 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 353.

Step 6: tert-butyl3-(3-(2-methylthiazol-5-yl)isoquinolin-8-yl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To the above step cooled solution was added tert-butyl3-bromo-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (100 mg, 0.2 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (19 mg, 0.02 mmol), K₃PO₄ (152 mg, 0.7 mmol), 1,4-dioxane(4 mL) and water (2 mL). The reaction mixture was heated to 90° C. for 4h under a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. DCM (60 mL) was addedand washed with water (50 mL×2), brine (50 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (DCM/MeOH=50:1)to give the title compound (55 mg, 41%) as a brown solid. LCMS M/Z (M+H)564.

Step 7:4-(3-(3-(2-methylthiazol-5-yl)isoquinolin-8-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-thiopyran1-oxide

To a solution of tert-butyl3-(3-(2-methylthiazol-5-yl)isoquinolin-8-yl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (55 mg, 0.1 mmol) in DCM (2 mL) was addedtrifluoroacetic acid (1.0 mL, 12 mmol). The mixture was stirred at roomtemperature for 2 h and concentrated in vacuo to give the title compound(40 mg, crude) as a yellow solid that required no further purification.LCMS M/Z (M+H) 464.

Step 8:N-methyl-3-(3-(2-methylthiazol-5-yl)isoquinolin-8-yl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

To a solution of4-(3-(3-(2-methylthiazol-5-yl)isoquinolin-8-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-thiopyran1-oxide (40 mg, 0.09 mmol) in DCM (3 mL) was added triethylamine (0.06mL, 0.43 mmol) and N-methyl-1H-imidazole-1-carboxamide (54 mg, 0.4mmol). The reaction was stirred at room temperature for 5 h andconcentrated in vacuo. DCM (30 mL) was added and washed with water (10mL×3), brine (10 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified byreverse phase chromatography (acetonitrile 20-50%/0.05% NH₄OH in water)to give the title compound (0.7 mg, 2%) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 7.98 (d, J=8.0Hz, 1H), 7.90-7.83 (m, 1H), 7.62 (d, J=7.2 Hz, 1H), 6.65-6.56 (m, 1H),4.65-4.54 (m, 1H), 4.42 (s, 2H), 3.76-3.67 (m, 2H), 2.95-2.89 (m, 2H),2.86-2.67 (m, 2H), 2.71 (s, 3H), 2.51-2.12 (m, 9H). LCMS M/Z (M+H) 521.

Example 461-(1-acetylpiperidin-4-yl)-N-methyl-3-(3-(2-methylthiazol-5-yl)isoquinolin-8-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

Step 1: 1-acetylpiperidin-4-yl methanesulfonate

To a solution of 1-(4-hydroxy-1-piperidyl)ethanone (200 mg, 1.4 mmol) inDCM (5 mL) at 0° C. was added triethylamine (212 mg, 2.1 mmol) andmethanesulfonyl chloride (480 mg, 4.19 mmol). The mixture was stirred at25° C. for 2 h. Water (50 mL) was added and the mixture was extractedwith DCM (50 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (300 mg, crude) as yellow oil that required no furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 4.98-4.92 (m, 1H), 3.83-3.81 (m,1H), 3.67-3.65 (m, 1H), 3.58-3.56 (m, 1H), 3.43-3.41 (m, 1H), 3.06 (s,3H), 2.01 (s, 3H), 2.00-1.88 (m, 4H).

Step 2: tert-butyl1-(1-acetylpiperidin-4-yl)-3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate A, 5.0 g, 16.6 mmol) in DMF (40 mL) was added Cs₂CO₃ (19.5g, 59.6 mmol) and 1-acetylpiperidin-4-yl methanesulfonate (5.5 g, 24.8mmol). The mixture was heated to 90° C. for 12 h under a nitrogenatmosphere. After cooling to room temperature, the mixture was filteredand concentrated in vacuo. DCM (100 mL) was added and washed with brine(80 mL×2). The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether:tert-butyl methyl ether:THF=from 10:1:1to 2:1:1) to give the title compound (2.0 g, 28%) as clear oil. ¹H NMR(400 MHz, DMSO-d₆) δ 4.50-4.41 (m, 1H), 4.38-4.29 (m, 1H), 4.16 (s, 2H),3.94-3.85 (m, 1H), 3.64-3.57 (m, 2H), 3.21-3.09 (m, 1H), 2.75-2.58 (m,3H), 2.03 (s, 3H), 1.91-1.80 (m, 3H), 1.73-1.61 (m, 1H), 1.41 (s, 9H).

Step 3: tert-butyl1-(1-acetylpiperidin-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl1-(1-acetylpiperidin-4-yl)-3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(500 mg, 1.17 mmol) in 1,4-dioxane (10 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (56 mg, 0.12mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (92 mg, 0.12 mmol), KOAc (345 mg, 3.51 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (740 mg,2.93 mmol). The mixture was heated to 80° C. for 2 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 475.

Step 4: tert-butyl1-(1-acetylpiperidin-4-yl)-3-(3-(2-methylthiazol-5-yl)isoquinolin-8-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To the above step cooled solution was added5-(8-chloroisoquinolin-3-yl)-2-methylthiazole (302 mg, 1.16 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (45 mg, 0.06 mmol), K₃PO₄ (738 mg, 3.48 mmol), 1,4-dioxane(5 mL) and water (3 mL). The reaction mixture was heated to 90° C. for12 h under a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. DCM (20 mL) was addedand washed with water (15 mL×2), brine (20 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (DCM/MeOH=20:1)to give the title compound (200 mg, 30%) as a yellow solid. LCMS M/Z(M+H) 573.

Step 5:1-(4-(3-(3-(2-methylthiazol-5-yl)isoquinolin-8-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethanone

To a solution of tert-butyl1-(1-acetylpiperidin-4-yl)-3-(3-(2-methylthiazol-5-yl)isoquinolin-8-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(200 mg, 0.35 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.27mL, 3.6 mmol). The mixture was stirred at room temperature for 2 h andconcentrated in vacuo to give the title compound (100 mg, crude) asyellow oil that required no further purification. LCMS M/Z (M+H) 473.

Step 6:1-(1-acetylpiperidin-4-yl)-N-methyl-3-(3-(2-methylthiazol-5-yl)isoquinolin-8-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

To a solution of1-(4-(3-(3-(2-methylthiazol-5-yl)isoquinolin-8-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethanone(100 mg, 0.21 mmol) in DCM (2 mL) was added triethylamine (0.1 mL, 0.70mmol) and N-methyl-1H-imidazole-1-carboxamide (58 mg, 0.47 mmol). Thereaction was stirred at room temperature for 12 h and concentrated invacuo. The crude residue was purified by reverse phase chromatography(acetonitrile 30-60%/0.05% NH₄OH in water) to give the title compound(62 mg, 55%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.58 (s, 1H),8.16 (s, 1H), 7.93 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.73-7.68 (m, 1H),7.51 (d, J=7.2 Hz, 1H), 4.83-4.78 (m, 1H), 4.65-4.59 (m, 1H), 4.34 (s,2H), 4.32-4.22 (m, 1H), 4.07-4.00 (m, 1H), 3.94-3.82 (m, 2H), 3.30-3.21(m, 1H), 2.88-2.83 (m, 2H), 2.78 (d, J=4.8 Hz, 1H), 2.76 (s, 3H),2.42-2.30 (m, 1H), 2.21-2.00 (m, 6H). LCMS M/Z (M+H) 530.

Example 473-isopropyl-N-methyl-1-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxamide

Step 1: ethyl 2-(benzyl(3-cyanopropyl)amino)acetate

To a solution of ethyl 2-(benzylamino)acetate (50 g, 258.7 mmol) andK₂CO₃ (71.5 g, 517.5 mmol) in MeCN (500 mL) was added4-bromobutyronitrile (28.7 mL, 284.6 mmol) dropwise. The mixture washeated to 80° C. for 12 h under a nitrogen atmosphere. After cooling toroom temperature, the mixture was filtered and concentrated in vacuo.The crude residue was purified by silica gel chromatography (petroleumether/EtOAc=5:1) to give the title compound (56 g, 83%) as light yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.28 (m, 5H), 4.18 (q, J=7.2 Hz,2H), 3.80 (s, 2H), 3.32 (s, 2H), 2.80 (t, J=6.4 Hz, 2H), 2.47 (t, J=7.2Hz, 2H), 1.87-1.77 (m, 2H), 1.29 (t, J=7.2 Hz, 3H).

Step 2: ethyl 2-((tert-butoxycarbonyl)(3-cyanopropyl)amino)acetate

To a solution of ethyl 2-(benzyl(3-cyanopropyl)amino)acetate (22 g, 84.5mmol) and Boc₂O (38.8 mL, 169 mmol) in EtOH (150 mL) was added 10% Pd/C(2.3 g). The mixture was stirred at room temperature for 6 h under ahydrogen atmosphere (40 Psi). The mixture was filtered and the filtratewas concentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=3:1) to give the title compound(17 g, 74%) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.25-4.14 (m,2H), 3.94-3.82 (m, 2H), 3.43-3.39 (m, 2H), 2.49-2.41 (m, 2H), 1.96-1.84(m, 2H), 1.51-1.37 (m, 9H), 1.30-1.27 (m, 2H).

Step 3: tert-butyl 4-cyano-3-oxopiperidine-1-carboxylate

To a solution of t-BuOK (8.5 g, 75.5 mmol) in toluene (100 mL) at 0° C.was added ethyl 2-((tert-butoxycarbonyl)(3-cyanopropyl)amino)acetate (17g, 62.9 mmol). The mixture was stirred at room temperature for 30 minunder a nitrogen atmosphere. Sat. aq. NH₄Cl (200 mL) was added andwashed with hexanes (200 mL). The aqueous phase was acidified with HCl(2 N) to pH 6 and then extracted with EtOAc (200 mL×2). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (13 g, 92%) as yellowoil that required no further purification.

Step 4: tert-butyl3-amino-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate

A mixture of tert-butyl 4-cyano-3-oxopiperidine-1-carboxylate (13 g,57.9 mmol) and hydrazine mono-hydrate (85%, 6.6 mL, 116 mmol) in EtOH(100 mL) was heated to 60° C. for 3 h. The mixture was concentrated invacuo to give the crude product that was dissolved in EtOAc (150 mL) andwashed with sat. aq. Na₂CO₃ (100 mL), water (100 mL). The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (DCM/MeOH=20:1)to give the title compound (10 g, 72%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 4.28 (s, 2H), 3.48 (d, J=5.6 Hz, 2H), 2.27 (d, J=5.6 Hz,2H), 1.40 (s, 9H).

Step 5: tert-butyl3-bromo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate

To a stirred mixture of tert-butyl3-amino-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (10 g,42 mmol), CuBr₂ (10.3 g, 46.2 mmol) in MeCN (80 mL) at 0° C. was addedisopentyl nitrite (7.4 mL, 54.6 mmol) dropwise and the reaction mixturestirred for 20 min. The temperature was raised to 60° C. and thereaction mixture was stirred for an additional 5 h. After cooling thereaction to room temperature, the reaction mixture was quenched withwater (200 mL) and the mixture was extracted with EtOAc (200 mL×2). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=1:1) to give the title compound (6g, 47%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 4.45 (s, 2H), 3.55(d, J=5.6 Hz, 2H), 2.35 (d, J=5.6 Hz, 2H), 1.41 (s, 9H).

Step 6: tert-butyl3-(prop-1-en-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate

To a solution of tert-butyl3-bromo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (2 g,6.6 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (484 mg, 0.7mmol), Na₂CO₃ (2.1 g, 19.9 mmol) and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.6 g, 33.1mmol). The mixture was heated to 100° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. EtOAc (150 mL) was added andwashed with water (140 mL×2). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=3:1) togive the title compound (1.3 g, 73%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.72-12.35 (m, 1H), 5.23 (s, 1H), 5.08 (s, 1H), 4.41 (s,2H), 3.60-3.49 (m, 2H), 2.67-2.55 (m, 2H), 2.05 (s, 3H), 1.41 (s, 9H).

Step 7: tert-butyl3-isopropyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate

a solution of tert-butyl3-(prop-1-en-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate(1.2 g, 4.6 mmol) in MeOH (8 mL) was added 10% Pd/C (485 mg). Themixture was stirred at room temperature for 12 h under a hydrogenatmosphere (15 Psi). The mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (860 mg, 71%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.24 (s, 1H), 4.37 (s, 2H),3.52 (d, J=6.0 Hz, 2H), 2.98-2.85 (m, 1H), 2.48 (d, J=6.0 Hz, 2H), 1.41(s, 9H), 1.18 (d, J=7.2 Hz, 6H).

Step 8: tert-butyl3-isopropyl-1-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate

To a solution of tert-butyl3-isopropyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate(240 mg, 0.9 mmol) in toluene (8 mL) was addedtris(dibenzylideneacetone)-dipalladium (83 mg, 0.09 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (38 mg, 0.09mmol), t-BuONa (261 mg, 2.7 mmol) and8-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline (286 mg, 1.2 mmol).The mixture was heated to 110° C. for 12 h under a nitrogen atmosphere.After cooling the reaction to room temperature, the mixture was filteredand concentrated in vacuo. EtOAc (50 mL) was added and washed with water(40 mL) and brine (40 mL). The organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=2:1) togive the title compound (150 mg, 35%) as a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 9.02 (s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.89-7.76 (m,2H), 7.73-7.59 (m, 1H), 7.44 (d, J=7.6 Hz, 1H), 4.36 (s, 2H), 3.99 (s,3H), 3.76-3.67 (m, 2H), 3.12-3.05 (m, 1H), 2.76-2.67 (m, 2H), 1.44 (s,9H), 1.37 (d, J=6.4 Hz, 6H).

Step 9:8-(3-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline

To a solution of tert-butyl3-isopropyl-1-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate(150 mg, 0.32 mmol) in DCM (0.5 mL) was added trifluoroacetic acid (0.46mL, 6.35 mmol). The mixture was stirred at room temperature for 12 h andconcentrated in vacuo to give the title compound (120 mg, crude) asbrown oil that required no further purification. LCMS M/Z (M+H) 373.

Step 10:3-isopropyl-N-methyl-1-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxamide

To a solution of8-(3-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline(120 mg, 0.32 mmol) in DCM (2 mL) was added triethylamine (0.09 mL, 0.64mmol) and N-methyl-1H-imidazole-1-carboxamide (81 mg, 0.64 mmol). Thereaction was stirred at room temperature for 12 h and concentrated invacuo. DCM (50 mL) was added and washed with water (40 mL), brine (40mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by Prep-TLC(DCM/MeOH=10:1) to give the title compound (62 mg, 45%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 8.99 (s, 1H), 8.03 (s, 1H), 8.00 (s,1H), 7.83 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.70-7.66 (m, 1H), 7.43 (d,J=7.6 Hz, 1H), 4.62-4.46 (m, 1H), 4.35 (s, 2H), 3.97 (s, 3H), 3.65 (d,J=5.6 Hz, 2H), 3.12-3.02 (m, 1H), 2.77 (d, J=4.4 Hz, 3H), 2.74 (d, J=5.6Hz, 2H), 1.35 (d, J=6.8 Hz, 6H). LCMS M/Z (M+H) 430.

Example 48N-methyl-1-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-3-morpholino-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxamide

Step 1:3-(1-methyl-1H-pyrazol-4-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline

To a solution of 8-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline (10.0g, 41.04 mmol) in 1,4-dioxane (220 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (1.96 g, 4.1mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (3.23 g, 4.1 mmol), KOAc (10.1 g, 102.59 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (31.26 g,123.11 mmol). The mixture was heated to 90° C. for 1 h under a nitrogenatmosphere. After cooling to room temperature, EtOAc (400 mL) was addedand washed with water (200 mL×2). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica gel chromatography (petroleum ether/EtOAc=1:1) togive the title compound (11.0 g, 22% purity) as a brown solid thatrequired no further purification. LCMS M/Z (M+H) 336.

Step 2: (3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)boronic acid

To a solution of3-(1-methyl-1H-pyrazol-4-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(10 g, crude) in acetone (50 mL) and water (50 mL) was added NaIO₄ (16.0g, 74.6 mmol) and NH₄OAc (5.7 g, 74.6 mmol). The mixture was stirred atroom temperature for 48 h. The reaction was filtered and concentrated invacuo. EtOAc (100 mL) was added and washed with water (70 mL), brine (70mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=10:1) to give the title compound (440 mg, 4%over 2 steps) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s,1H), 8.57-8.51 (m, 2H), 8.31 (s, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.87(d, J=8.4 Hz, 1H), 7.78 (d, J=5.6 Hz, 1H), 7.73-7.63 (m, 1H), 3.91 (s,3H).

Step 3: tert-butyl3-bromo-1-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate

To a solution of tert-butyl3-bromo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (400mg, 1.3 mmol) in THF (10 mL) was added(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)boronic acid (469 mg, 1.6mmol), triethylamine (0.92 mL, 6.6 mmol), pyridine (1.43 mL, 13.2 mmol)and copper(II) acetate (721 mg, 4.0 mmol). The mixture was heated to 60°C. for 12 h under an oxygen atmosphere. After cooling to roomtemperature, the mixture was filtered and concentrated in vacuo. EtOAc(100 mL) was added and washed with water (80 mL×2), brine (80 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The crude residue was purified by silica gel chromatography(petroleum ether/EtOAc=1:1) to give the title compound (100 mg, 15%) asa yellow solid. LCMS M/Z (M+H) 511.

Step 4: tert-butyl1-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-3-morpholino-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate

To a solution of tert-butyl3-bromo-1-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate(100 mg, 0.2 mmol) in 1,4-dioxane (4 mL) wasdichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II),t-BuONa (57 mg, 0.6 mmol) and morpholine (0.035 mL, 0.4 mmol). Themixture was heated to 110° C. for 16 h under an argon atmosphere. Aftercooling to room temperature, DCM (50 mL) was added and washed with water(40 mL×2), brine (40 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=1:1) togive the title compound (42 mg, 41%) as a yellow solid. LCMS M/Z (M+H)516.

Step 5:4-(1-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)morpholine

To a solution of tert-butyl1-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-3-morpholino-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate(42 mg, 0.08 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.06mL, 0.8 mmol). The mixture was stirred at room temperature for 3 h andconcentrated in vacuo to give the title compound (35 mg, crude) as brownoil that required no further purification. LCMS M/Z (M+H) 416.

Step 6:N-methyl-1-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-3-morpholino-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxamide

To a solution of4-(1-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)morpholine(35 mg, 0.08 mmol) in DCM (3 mL) was added triethylamine (0.04 mL, 0.25mmol) and N-methyl-1H-imidazole-1-carboxamide (16 mg, 0.13 mmol). Thereaction was stirred at room temperature for 12 h and concentrated invacuo. EtOAc (50 mL) was added and washed with water (40 mL×2). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The crude residue was purified by reverse phase chromatography(acetonitrile 17-47%/0.05% HCl in water) to give the title compound (6mg, 15%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1H),8.49 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 8.01 (d, J=8.4 Hz, 1H),7.98-7.90 (m, 1H), 7.62 (d, J=6.8 Hz, 1H), 6.61 (s, 1H), 4.43 (s, 2H),3.94 (s, 3H), 3.76-3.70 (m, 4H), 3.65-3.55 (m, 2H), 3.23-3.13 (m, 4H),2.65-2.55 (m, 2H), 2.52 (s, 3H). LCMS M/Z (M+H) 473.

Example 492-cyano-N-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-5(4H)-carboxamide

Step 1: 2-((tetrahydro-2H-pyran-4-yl)amino)acetonitrile

To a solution of tetrahydro-2H-pyran-4-amine hydrochloride (45 g, 327mmol) and K₂CO₃ (135.6 g, 981 mmol) in MeCN (300 mL) was added2-chloroacetonitrile (24.9 mL, 392 mmol) dropwise. The mixture washeated to 80° C. for 16 h under a nitrogen atmosphere. After cooling toroom temperature, the mixture was filtered and concentrated in vacuo.The crude residue was purified by silica gel chromatography (petroleumether/EtOAc=1:1) to give the title compound (26 g, 57%) as brown oil. ¹HNMR (400 MHz, CDCl₃) δ 3.95-3.88 (m, 2H), 3.59 (s, 2H), 3.42-3.35 (m,2H), 2.95-2.82 (m, 1H), 1.82-1.68 (m, 2H), 1.42-1.29 (m, 2H).

Step 2: tert-butyl3-cyano-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (21 g,93.6 mmol) in DCM (200 mL) at 0° C. was added triethylamine (17 mL, 121mmol), N,N-dimethylpyridin-4-amine (2.3 g, 18.7 mmol) andtrifluoromethanesulfonic anhydride (20.4 mL, 121 mmol). The reaction wasstirred at room temperature for 6 h. DCM (100 mL) was added and washedwith water (200 mL), brine (200 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica gel chromatography (petroleum ether/EtOAc=3:1) togive the title compound (20 g, 60%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 4.26 (s, 2H), 3.62-3.56 (m, 2H), 2.73-2.62 (m, 2H), 1.42 (s,9H).

Step 3: tert-butyl3-amino-2-cyano-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-cyano-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate(5 g, 14 mmol) in t-BuOH (70 mL) was added2-((tetrahydro-2H-pyran-4-yl)amino)acetonitrile (2.4 g, 16.8 mmol) andCs₂CO₃ (13.7 g, 42 mmol). The mixture was heated to 90° C. for 16 hunder a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. EtOAc (250 mL) was addedand washed with water (200 mL×2), brine (200 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (petroleumether/EtOAc=1:1) to give the title compound (270 mg, 6%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 4.23 (s, 2H), 4.15-4.09 (m, 2H),4.06-4.00 (m, 1H), 3.75-3.65 (m, 2H), 3.55-3.41 (m, 4H), 2.70-2.58 (m,2H), 2.41-2.30 (m, 2H), 1.84-1.74 (m, 2H), 1.48 (s, 9H). LCMS M/Z (M+H)347.

Step 4: tert-butyl3-bromo-2-cyano-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-5(4H-carboxylate

To a stirred mixture of tert-butyl3-amino-2-cyano-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-5(4H)-carboxylate(510 mg, 1.47 mmol), CuBr₂ (428 mg, 1.91 mmol) in MeCN (30 mL) at 0° C.was added isopentyl nitrite (0.26 mL, 1.91 mmol) dropwise and thereaction mixture stirred for 20 min. The temperature was raised to 60°C. and the reaction mixture was stirred for an additional 5 h. Aftercooling the reaction to room temperature, the reaction mixture wasquenched with water (60 mL) and the mixture was extracted with EtOAc (60mL×2). The combined organic layers were washed with brine (40 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (petroleumether/EtOAc=3:2) to give the title compound (170 mg, 28%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 4.28 (s, 2H), 4.24-4.18 (m, 1H),4.16-4.12 (m, 2H), 3.80-3.68 (m, 2H), 3.51-3.45 (m, 2H), 2.78-2.68 (m,2H), 2.51-2.33 (m, 2H), 1.87-1.80 (m, 2H), 1.50 (s, 9H).

Step 5: tert-butyl2-cyano-3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-2-cyano-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-5(4H)-carboxylate(170 mg, 0.41 mmol) in THF (15 mL) and water (3 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (20 mg, 0.041mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (33 mg, 0.041 mmol), Na₂CO₃ (134 mg, 1.24 mmol) and3-(1-methyl-1H-pyrazol-4-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(181 mg, 0.54 mmol). The mixture was heated to 60° C. for 12 h under anitrogen atmosphere. After cooling to room temperature, the mixture wasfiltered and concentrated in vacuo. EtOAc (55 mL) was added and washedwith water (40 mL×2). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified bysilica gel chromatography (petroleum ether/EtOAc=3:2) to give the titlecompound (192 mg, 86%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.07(s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.86-7.78 (m, 2H), 7.71-7.66 (m,1H), 7.46 (d, J=6.8 Hz, 1H), 4.46-4.32 (m, 1H), 4.29-4.08 (m, 4H),4.05-3.65 (m, 5H), 3.58-3.52 (m, 2H), 2.93-2.80 (m, 2H), 2.58-2.49 (m,2H), 2.01-1.94 (m, 2H), 1.62 (s, 9H). LCMS M/Z (M+H) 539.

Step 6:3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbonitrile

To a solution of tert-butyl2-cyano-3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-5(4H)-carboxylate (192 mg, 0.36 mmol) in DCM (0.5 mL) was addedtrifluoroacetic acid (0.52 mL, 7.12 mmol). The mixture was stirred atroom temperature for 3 h and concentrated in vacuo to give the titlecompound (145 mg, crude) as brown oil that required no furtherpurification. LCMS M/Z (M+H) 439.

Step 7:2-cyano-N-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-5(4H)-carboxamide

To a solution of3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbonitrile(145 mg, 0.33 mmol) in DCM (3 mL) was added triethylamine (0.1 mL, 0.66mmol) and N-methyl-1H-imidazole-1-carboxamide (83 mg, 0.66 mmol). Thereaction was stirred at room temperature for 12 h and concentrated invacuo. DCM (30 mL) was added and washed with water (30 mL×2). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=10:1) togive the title compound (73 mg, 55%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 9.05 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.86-7.80 (m, 2H),7.73-7.68 (m, 1H), 7.46 (d, J=6.4 Hz, 1H), 4.46-4.32 (m, 2H), 4.25-4.15(m, 2H), 4.12-3.95 (m, 6H), 3.75-3.64 (m, 1H), 3.55 (t, J=12.0 Hz, 2H),2.96-2.84 (m, 2H), 2.73 (d, J=3.6 Hz, 3H), 2.62-2.45 (m, 2H), 2.03-1.93(m, 2H). LCMS M/Z (M+H) 496.

Example 508-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)imidazo[1,2-a]pyridine-2-carboxylicacid

To a solution of methyl8-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)imidazo[1,2-a]pyridine-2-carboxylate(50 mg, 0.15 mmol), obtained in a similar fashion as procedure S, in THF(0.35 mL) was added lithium chloride (3.3 mg, 0.078 mmol) and sodiumhydroxide 3.7 mol/L in water (77 μL). The mixture was stirred at 55° C.for 3 h. The reaction mixture was then cooled to room temperature,concentrated HCl was added (20 μL) and the solution was concentrated invacuo. The mixture obtained was purified by reverse phase chromatography(acetonitrile 2-20%/0.1% ammonium hydroxide in water) to give the titlecompound (5.0 mg, 17%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 22/23H) δ 8.58 (dt, J=6.9, 1.5 Hz, 1H), 8.47 (s, 1H), 7.53-7.40 (m, 1H), 7.03(td, J=6.9, 3.8 Hz, 1H), 4.89 (s, 1H), 4.60 (s, 1H), 4.39 (tq, J=11.9,4.2 Hz, 1H), 3.98 (dt, J=10.1, 4.6 Hz, 2H), 3.79 (t, J=6.0 Hz, 2H),3.55-3.43 (m, 2H), 2.95-2.75 (m, 2H), 2.19-2.01 (m, 5H), 1.87 (dt,J=13.5, 3.3 Hz, 2H). LCMS M/Z (M+H) 410.

Example 511-(3-(2-(pyridin-3-yl)-1H-benzo[d]imidazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

Step 1: 4-chloro-2-(pyridin-3-yl)-1H-benzo[d]imidazole

To a solution of pyridine-3-carbonyl chloride hydrochloride (157 mg,0.884 mmol) and trimethylamine (224 mg, 2.21 mmol) in DCM (5.3 mL) wasadded 3-chlorobenzene-1,2-diamine (105 mg, 0.736 mmol). The mixture wasstirred at room temperature for 16 h. The reaction mixture was thencooled to room temperature and saturated aqueous NaHCO₃ solution (20 mL)and brine solution (5 mL) were added and the two layers were separated.The aqueous layer was washed with DCM (2×10 mL). The combined organiclayers were dried over anhydrous MgSO₄, filtered and concentrated invacuo. The residue obtained was dissolved in acetic acid (1.8 mL) andconcentrated HCl was added (60 μL, 0.74 mmol). The mixture was stirredat 100° C. for 2 h. The reaction mixture was then cooled to roomtemperature and concentrated in vacuo. The crude residue was partitionedbetween DCM (20 mL) and saturated aqueous NaHCO₃ solution (20 mL). Thetwo phases were separated and the aqueous layer was extracted with DCM(2×15 mL). The combined organic layers were washed with brine, driedover anhydrous MgSO₄, filtered and concentrated in vacuo. The mixtureobtained was purified by silica gel chromatography (acetone/heptane=1:19to 2:3) to give the title compound (97.4 mg, 58%) as a beige solid. ¹HNMR (400 MHz, DMSO-d₆, 7/8 H) δ 8.75 (dd, J=4.8, 1.7 Hz, 1H), 7.53-7.45(m, 1H), 7.39-7.27 (m, 2H), 9.30 (dd, J=2.3, 1.0 Hz, 1H), 8.42 (dt,J=8.0, 2.0 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H). LCMS M/Z (M+H) 230.

Step 2:1-(3-(2-(pyridin-3-yl)-1H-benzo[d]imidazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

To a solution of1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone(Intermediate H, 50 mg, 0.15 mmol) and bis(pinacolato)diboron (77 mg,0.30 mmol) in dioxane (0.76 mL) was added KOAc (45 mg, 0.46 mmol),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (3.7 mg, 0.0046 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (4.4 mg, 0.0091mmol). The mixture was stirred at 80° C. for 16 h under a nitrogenatmosphere. The reaction mixture was cooled to room temperature and4-chloro-2-(3-pyridyl)-1H-benzimidazole (30 mg, 0.13 mmol), K₃PO₄.H₂O(40 mg, 0.19 mmol), water (0.3 mL) and(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (3.7 mg, 0.0046 mmol) were added. The reaction mixturewas stirred at 90° C. for 4 h under a nitrogen atmosphere. The reactionmixture was then cooled to room temperature and concentrated in vacuo.The crude residue was dissolved in dichloromethane (5 mL), dried overanhydrous MgSO₄, filtered through celite and concentrated in vacuo. Themixture obtained was purified by reverse phase chromatography(acetonitrile 5-50%/0.1% ammonium hydroxide in water) to give the titlecompound (30.4 mg, 45%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ13.49-12.78 (m, 1H), 9.52-9.31 (m, 1H), 8.68 (dt, J=3.9, 1.6 Hz, 1H),8.60 (s, 1H), 7.60 (dt, J=8.1, 4.3 Hz, 2H), 7.45 (s, 1H), 7.34-7.29 (m,1H), 4.85 (s, 2H), 4.41 (s, 1H), 4.04-3.97 (m, 2H), 3.88-3.77 (m, 2H),3.51 (t, J=11.8 Hz, 2H), 3.39-3.33 (m, 2H), 2.99-2.79 (m, 2H), 2.25-2.07(m, 2H), 2.01 (s, 1H), 1.91 (d, J=12.7 Hz, 2H). LCMS M/Z (M+H) 443.

Example 52N-methyl-3-(2-(1-methyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

Step 1: 6-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one

To a solution of 5-bromo-1-tetralone (3.0 g, 13.33 mmol) in conc. HCl(30 mL) at 0° C. was added sodium azide (1.79 g, 27.53 mmol)portionwise. The reaction mixture was heated to 50° C. for 16 h under anitrogen atmosphere. After cooling to room temperature, the mixture wasbasified with K₂CO₃ (1 M) to pH 10 and then extracted with EtOAc (100mL×2). The combined organic layers were washed with sat. aq. NaHCO₃ (50mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The crude residue was purified by silica gel chromatography (petroleumether/EtOAc=3:2) to give the title compound (1.2 g, 37%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.22-8.13 (m, 1H), 7.75-7.71 (m, 1H),7.48 (d, J=6.8 Hz, 1H), 7.29-7.25 (m, 1H), 2.93 (t, J=6.8 Hz, 2H),2.90-2.84 (m, 2H), 1.90-1.82 (m, 2H).

Step 2:6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one

To a solution of 6-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (1.5g, 6.25 mmol) in 1,4-dioxane (50 mL) was added copper(I) iodide (119 mg,0.62 mmol), (1R,2R)-cyclohexane-1,2-diamine (142 mg, 1.25 mmol), K₃PO₄(3.9 g, 18.74 mmol) and 4-iodo-1-methyl-1H-pyrazole (1.95 g, 9.37 mmol).The reaction mixture was heated to 120° C. for 48 h under a nitrogenatmosphere. After cooling to room temperature, the mixture was filteredand concentrated in vacuo. Water (100 mL) was added and extracted withEtOAc (50 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (DCM/MeOH=20:1) to give the titlecompound (900 mg, 45%) as a yellow solid. LCMS M/Z (M+H) 320.

Step 3:6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine

To a solution of6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one(900 mg, 2.81 mmol) in THF (50 mL) was added borane dimethyl sulfidecomplex (1.41 mL, 14.1 mmol, 10 M). The reaction mixture was heated to70° C. for 16 h under a nitrogen atmosphere. After cooling to roomtemperature, the reaction was quenched with MeOH (20 mL) and heated to70° C. for an additional 1 h. After cooling to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (DCM/MeOH=10:1) to give the titlecompound (700 mg, 81%) as gray oil. LCMS M/Z (M+H) 306.

Step 4: tert-butyl1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Intermediate G, 400 mg, 1.04 mmol) in 1,4-dioxane (8 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (30 mg, 0.06mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (25 mg, 0.03 mmol), KOAc (300 mg, 3.12 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (526 mg,2.08 mmol). The mixture was heated to 80° C. for 2 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 434.

Step 5: tert-butyl3-(2-(1-methyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

To the above step cooled solution was added6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine(141 mg, 0.46 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (25 mg, 0.03 mmol), K₃PO₄ (244 mg, 1.15 mmol), 1,4-dioxane(2 mL) and water (2 mL). The reaction mixture was heated to 90° C. for 1h under a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. Water (50 mL) was addedand extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine (30 mL×3), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=20:1) to give the title compound (150 mg, 27%)as a yellow solid. LCMS M/Z (M+H) 533.

Step 6:2-(1-methyl-1H-pyrazol-4-yl)-6-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine

To a solution of tert-butyl3-(2-(1-methyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(150 mg, 0.28 mmol) in DCM (10 mL) at 0° C. was added trifluoroaceticacid (0.42 mL, 5.63 mmol). The mixture was stirred at 0° C. for 2 h andconcentrated in vacuo to give the title compound (120 mg, crude) asbrown oil that required no further purification. LCMS M/Z (M+H) 433.

Step 7:N-methyl-3-(2-(1-methyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

To a solution of2-(1-methyl-1H-pyrazol-4-yl)-6-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine(120 mg, 0.28 mmol) in DCM (15 mL) was added triethylamine (0.12 mL,0.83 mmol) and N-methyl-1H-imidazole-1-carboxamide (69 mg, 0.55 mmol).The reaction was stirred at room temperature for 16 h. DCM (40 mL) wasadded and washed with brine (30 mL×3). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 8-38%/0.2%formic acid in water) to give the title compound (38 mg, 28%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.21 (m, 1H), 7.17-7.07 (m, 3H),6.79 (s, 1H), 4.42 (s, 2H), 4.25-4.08 (m, 5H), 3.83 (t, J=5.2 Hz, 2H),3.76 (s, 3H), 3.58-3.48 (m, 4H), 3.02-2.95 (m, 2H), 2.85-2.75 (m, 5H),2.39-2.25 (m, 2H), 1.92-1.84 (m, 2H), 1.82-1.74 (m, 2H). LCMS M/Z (M+H)490.

Example 531-(3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)ethan-1-one

Step 1:5-benzyl-1-(triisopropylsilyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

To a solution of 5-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine(1.50 g, 7.06 mmol) in THF (18 mL) at 0° C. was added sodium hydride 60%in mineral oil (424 mg, 10.6 mmol). The solution was stirred at 0° C.for 30 min, followed by the addition of triisopropylsilyl chloride (1.82mL, 8.48 mmol). The mixture was stirred at 0° C. for 15 min and thenheated at 60° C. for 2 h. The reaction mixture was then cooled to roomtemperature and concentrated in vacuo. Water (50 mL) and iPrOAc (50 mL)were added and the two layers were separated. The aqueous layer wasextracted with iPrOAc (40 mL). The combined organic layers were driedover anhydrous MgSO₄, filtered and concentrated in vacuo. The residueobtained was purified by silica gel chromatography (iPrOAc/heptane=1:9)to give the title compound (2.60 g, quant.) as a pale yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 7.43-7.20 (m, 5H), 6.67 (d, J=2.9 Hz, 1H), 6.00 (d,J=2.8 Hz, 1H), 3.69 (s, 2H), 3.54 (s, 2H), 2.73 (s, 4H), 1.60-1.54 (m,2H), 1.51-1.39 (m, 3H), 1.10 (d, J=7.5 Hz, 18H). LCMS M/Z (M+H) 369.

Step 2:1-(triisopropylsilyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

To a 100 mL round bottom flask was added5-benzyl-1-(triisopropylsilyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine(1.00 g, 2.71 mmol) and palladium 10% on carbon (433 mg, 0.407 mmol) inEtOH (9.0 mL) and AcOH (2.7 mL). The solution was purged three timeswith hydrogen gas and stirred at 30° C. for 4 h under 1 atm of hydrogen.The hydrogen was removed in vacuo, the reaction mixture was filteredthrough celite and the solvent was concentrated in vacuo to afford thetitle compound (870 mg, quant.) as an orange oil. ¹H NMR (400 MHz,CDCl₃) δ 6.73 (d, J=2.9 Hz, 1H), 6.06 (d, J=2.8 Hz, 1H), 4.15 (s, 2H),3.39 (t, J=6.0 Hz, 2H), 2.96 (t, J=5.8 Hz, 2H), 1.51-1.39 (m, 3H), 1.10(d, J=7.4 Hz, 18H). LCMS M/Z (M+H) 279.

Step 3:1-(1-(triisopropylsilyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)ethan-1-one

To a solution of1-(triisopropylsilyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (1.50g, 7.06 mmol) in DCM (6.2 mL) at 0° C. was added triethylamine (947 mg,9.36 mmol) followed by acetic anhydride (382 mg, 3.74 mmol). Thesolution was stirred at room temperature for 2 h. To the reactionmixture was then added saturated aqueous NaHCO₃ solution (40 mL) and DCM(10 mL) and the two layers were separated. The aqueous layer was washedwith DCM (2×30 mL). The combined organic layers were washed with brine,dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Theresidue obtained was purified by silica gel chromatography(iPrOAc/heptane=3:7) to give the title compound (837 mg, 84%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 6.76-6.68 (m, 1H), 6.07 (d, J=2.8 Hz,1H), 4.63-4.46 (m, 2H), 3.90-3.63 (m, 2H), 2.82-2.68 (m, 2H), 2.19-2.11(m, 3H), 1.56-1.39 (m, 3H), 1.13-1.07 (m, 18H). LCMS M/Z (M+H) 321.

Step 4:1-(3-bromo-1-(triisopropylsilyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)ethan-1-one

To a solution of1-(1-(triisopropylsilyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)ethan-1-one(400 mg, 1.25 mmol) in THF (4.2 mL) at −78° C. under a nitrogenatmosphere was added N-bromosuccinimide (244 mg, 1.37 mmol). Thereaction mixture was stirred at −78° C. for 2 h30. The reaction mixturewas then added to stirring MeOH (30 mL) at −78° C. and the the mixturewas concentrated in vacuo. Water (40 mL) and iPrOAc (40 mL) and the twolayers were separated. The aqueous layer was washed with iPrOAc (40 mL).The combined organic layers were washed with brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. The residue obtained waspurified by silica gel chromatography (iPrOAc/heptane=3:7 to 7:3) togive the title compound (239 mg, 48%) as a pale yellow oil. ¹H NMR (400MHz, CDCl₃) δ 6.74-6.66 (m, 1H), 4.55-4.32 (m, 2H), 3.88-3.61 (m, 2H),2.78-2.65 (m, 2H), 2.25-2.15 (m, 3H), 1.53-1.36 (m, 3H), 1.13-1.07 (m,18H). LCMS M/Z (M+H) 399.

Step 5:1-(3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(triisopropylsilyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)ethan-1-one

To a solution of1-(3-bromo-1-(triisopropylsilyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)ethan-1-one(225 mg, 0.563 mmol) and3-(1-methyl-1H-pyrazol-4-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(227 mg, 0.676 mmol) in 1,4-dioxane (1.9 mL) and water (0.47 mL) wasadded K₃PO₄.H₂O (334 mg, 1.41 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(23 mg, 0.028 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (13 mg, 0.028mmol). The mixture was stirred at 140° C. for 12 min in a microwaveunder a nitrogen atmosphere. The crude mixture was diluted in DCM (30mL), filtered through celite and concentrated in vacuo. The residueobtained was purified by silica gel chromatography (MeOH/DCM=1:9 to 3:7)to give the title compound (149 mg, 50%) as a brown-orange solid. ¹H NMR(400 MHz, CDCl₃) δ 9.31 (s, 1H), 8.07-7.84 (m, 2H), 7.86-7.56 (m, 3H),7.39 (dt, J=6.9, 1.3 Hz, 1H), 6.86 (d, J=2.3 Hz, 1H), 4.52-4.44 (m, 1H),4.33 (s, 1H), 3.98 (s, 3H), 3.94 (t, J=5.7 Hz, 1H), 3.76 (t, J=5.7 Hz,1H), 2.77-2.95 (m, 2H), 2.03-1.98 (m, 3H), 1.58-1.46 (m, 3H), 1.17 (dd,J=7.6, 2.6 Hz, 18H). LCMS M/Z (M+H) 528.

Step 6:1-(3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)ethan-1-one

To a solution of1-(3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(triisopropylsilyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)ethan-1-one(145 mg, 0.275 mmol) in THF (0.92 mL) was added tetrabutylammoniumfluoride 1 M in THF (0.330 mL, 0.330 mmol). The reaction mixture wasstirred at room temperature for 3 h. Water (2 mL) was added and themixture was concentrated in vacuo. The crude residue obtained wasdissolved in DMSO (2 mL), filtered and purified by reverse phasechromatography (acetonitrile 30-70%/0.1% formic acid in water) to givethe title compound (77 mg, 75%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃)δ 9.46 (d, J=13.6 Hz, 1H), 8.08-8.01 (m, 2H), 7.83 (d, J=5.3 Hz, 1H),7.78-7.62 (m, 2H), 7.41 (t, J=10.1, 6.7 Hz, 1H), 6.89 (s, 1H), 4.54 (s,1H), 4.37 (s, 1H), 3.99 (d, J=2.1 Hz, 4H), 3.81 (t, J=5.6 Hz, 1H),2.91-2.77 (m, 2H), 2.17 (s, 1H), 2.05-1.98 (m, 3H). LCMS M/Z (M+H) 372.

Step 7: tetrahydro-2H-pyran-4-yl trifluoromethanesulfonate

To a solution of tetrahydropyran-4-ol (270 mg, 2.64 mmol) in DCM (2.9mL) was added pyridine (230 mg, 2.91 mmol) followed bytrifluoromethanesulfonic anhydride (810 mg, 2.87 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 20 min. The reaction mixturewas filtered and the solid was washed with DCM (2 mL). The filtrate waswashed with water, 1.0 N HCl, water and brine. The organic layer wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo to affordthe title compound (462 mg, 76%) as a black liquid which was useddirectly in the next step. ¹H NMR (400 MHz, CDCl₃) δ 1.99 (m, 2H), 2.11(m, 2H), 3.58 (m, 2H), 3.96 (m, 2H), 5.17 (m, 1H).

Step 8:1-(3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)ethan-1-one

To a solution of1-(3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)ethan-1-one(75 mg, 0.202 mmol) in DMF (1.0 mL) was added sodium hydride 60% inmineral oil (9.7 mg, 0.24 mmol) at 0° C. followed bytetrahydro-2H-pyran-4-yl trifluoromethanesulfonate (200 mg, 0.854 mmol).The reaction mixture was slowly warmed up and stirred at roomtemperature for 2 h. Then, the reaction mixture was stirred at 150° C.for 10 min. The reaction mixture was cooled down to room temperature,diluted with DCM (10 mL), filtered through celite and concentrated invacuo. The crude residue obtained was dissolved in DMSO (2 mL), filteredand purified by reverse phase chromatography (acetonitrile 20-60%/0.1%ammonium hydroxide in water) to give the title compound (1.5 mg, 2%) asa yellow oil. LCMS M/Z (M+H) 456.

The following were prepared in a similar fashion to the above compounds:

Example Compound Name and Structure NMR; m/z Procedure Example 54

¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 7.55- 7.48 (m, 2H), 7.22-7.19(m, 1H), 4.79-4.75 (m, 2H), 3.99-3.68 (m, 5H), 2.93- 2.81 (m, 2H),2.24-2.16 (m, 3H); m/z 296. A Example 55

¹H NMR (400 MHz, CD₃OD) δ 7.44-7.42 (m, 1H), 7.30 (d, J = 6.0 Hz, 1H),7.20-7.16 (m, 1H), 7.09 (d, J = 7.2 Hz, 1H), 4.60-4.66 (m, 2H), 3.99-3.88 (m, 2H), 3.86 (s, 3H), 2.95-2.82 (m, 2H), 2.21- 2.08 (m, 3H); m/z295. A Example 56

¹H NMR (400 MHz, CDCl₃) δ 8.08-8.03 (m, 1H), 7.43- 7.40 (m, 2H),7.17-7.09 (m, 2H), 4.68-4.64 (m, 2H), 4.01-3.99 (m, 2H), 3.95- 3.85 (m,2H), 2.93-3.82 (m, 2H), 2.23-2.17 (m, 3H), 1.35-1.32 (m, 1H), 0.62- 0.59(m, 2H), 0.47-0.43 (m, 2H); m/z 335. A Example 57

¹H NMR (400 MHz, DMSO- d₆) δ 11.23 (s, 1H), 8.31- 8.20 (m, 1H),7.56-7.35 (m, 2H), 7.17-7.05 (m, 2H), 4.59 (s, 2H), 4.39-4.23 (m, 1H),4.08-3.95 (m, 2H), 3.80-3.74 (m, 2H), 3.50 (t, J = 12.0 Hz, 2H),2.91-2.71 (m, 2H), 2.22-2.09 (m, 5H), 1.90-1.78 (m, 2H); m/z 365. AExample 58

¹H NMR (400 MHz, DMSO- d₆) δ 8.24-8.19 (m, 1H), 7.54-7.47 (m, 2H), 7.20-7.16 (m, 1H), 7.10-7.06 (m, 1H), 4.84-4.77 (m, 1H), 4.60 (s, 2H),3.80-3.73 (m, 5H), 2.82-2.68 (m, 2H), 2.12 (s, 3H), 1.53-1.51 (m, 6H);m/z 337. B Example 59

¹H NMR (400 MHz, DMSO- d₆) δ 8.33-8.23 (m, 1H), 7.58-7.38 (m, 2H), 7.23-7.17 (m, 1H), 7.15-7.07 (m, 1H), 4.59 (s, 2H), 4.40-4.27 (m, 1H),4.07-3.95 (m, 2H), 3.85 (s, 3H), 3.83-3.71 (m, 2H), 3.50 (t, J = 12.0Hz, 2H), 2.90-2.71 (m, 2H), 2.23-2.08 (m, 5H), 1.93- 1.79 (m, 2H); m/z379. B Example 60

¹H NMR (400 MHz, CD₃OD): δ 8.22 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H),7.43- 7.38 (m, 3H), 4.69-4.65 (m, 2H), 3.99-3.85 (m, 2H), 3.93 (s, 3H),3.84 (s, 3H), 2.90-2.78 (m, 2H), 2.24- 2.16 (m, 3H); m/z 375. C Example61

¹H NMR (400 MHz, DMSO- d₆) δ 11.60 (s, 1H), 8.04 (s, 1H), 7.65-7.63 (m,2H), 7.06-7.02 (m, 1H), 4.64- 4.61 (m, 2H), 3.88 (s, 3H), 3.81-3.77 (m,5H), 2.86- 2.73 (m, 2H), 2.11-2.02 (m, 3H); m/z 353. C Example 62

¹H NMR (400 MHz, DMSO- d₆) δ 11.50 (s, 1H), 7.42 (s, 1H), 7.25-7.21 (m,1H), 7.08-7.00 (m, 2H), 4.61 (s, 2H), 3.80-3.75 (m, 5H), 2.86-2.71 (m,2H), 2.11- 2.04 (m, 3H); m/z 329. C Example 63

¹H NMR (400 MHz, DMSO- d₆) δ 10.94 (s, 1H), 7.19 (s, 1H), 6.88-6.84 (m,1H), 6.64-6.61 (m, 1H), 4.60 (s, 2H), 3.80-3.75 (m, 8H), 284-2.70 (m,2H), 2.10- 2.04 (m, 3H); m/z 325. C Example 64

¹H NMR (400 MHz, DMSO- d₆) δ 11.10 (s, 1H), 7.34- 7.32 (m, 1H),6.97-6.89 (m, 3H), 4.58 (s, 2H), 3.81-3.74 (m, 5H), 2.84-2.69 (m, 2H),2.10-2.02 (m, 3H); m/z 309. C Example 65

¹H NMR (400 MHz, CDCl₃) δ 7.81-7.79 (m, 2H), 7.67 (s, 1H), 7.45-7.27 (m,3H), 4.83-4.66 (m, 2H), 3.99 (s, 3H), 3.95-3.75 (m, 2H), 3.82 (s, 3H),2.80-2.72 (m, 2H), 2.21-2.15 (m, 3H); m/z 336. C Example 66

¹H NMR (400 MHz, DMSO- d₆) δ 11.10 (s, 1H), 7.33 (s, 1H), 7.01 (s, 1H),6.95-6.91 (m, 2H), 4.60 (s, 2H), 3.96 (d, J = 6.8 Hz), 3.81-3.74 (m,2H), 2.87-2.74 (m, 2H), 2.11- 2.04 (m, 3H), 1.29-1.25 (m, 1H), 0.55-0.52(m, 2H), 0.42- 0.40 (m, 2H); m/z 349. C Example 67

¹H NMR (400 MHz, DMSO- d₆) δ 11.15 (s, 1H), 7.39-7.36 (m, 2H), 7.18-7.14(m, 1H), 7.06-7.00 (m, 2H), 4.64 (s, 2H), 3.98 (d, J = 7.2 Hz), 3.82-3.76 (m, 2H), 2.89-2.76 (m, 2H), 2.12-2.07 (m, 3H), 1.29- 1.25 (m, 1H),0.55-0.52 (m, 2H), 0.45-0.41 (m, 2H); m/z 335. C Example 68

¹H NMR (400 MHz, DMSO- d₆) δ 11.25 (s, 1H), 8.29-8.23 (m, 1H), 8.07 (s,1H), 7.81 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 7.32-7.30 (m, 1H), 5.52-5.48 (m, 1H), 5.08-5.04 (m, 2H), 4.91-4.87 (m, 2H), 4.56 (s, 2H), 3.85(s, 3H), 3.75- 3.69 (m, 2H), 2.77-2.64 (m, 2H), 2.09-1.94 (m, 3H); m/z417. C Example 69

¹H NMR (400 MHz, DMSO- d₆) δ 11.29 (s, 1H), 8.17-8.12 (m, 1H), 8.06 (s,1H), 7.81 (s, 1H), 7.50 (s, 1H), 7.48-7.36 (m, 1H), 7.29-7.26 (m, 1H),5.02-4.91 (m, 1H), 4.56 (s, 2H), 4.12-4.03 (m, 2H), 3.92- 3.87 (m, 2H),3.85 (s, 3H), 3.79-3.68 (m, 2H), 2.89- 2.68 (m, 2H), 2.41-2.23 (m, 2H),2.10 (s, 3H); m/z 431. C Example 70

¹H NMR (400 MHz, DMSO- d₆) δ 11.11 (s, 1H), 8.07 (s, 1H), 7.81 (s, 1H),7.43 (s, 1H), 7.42-7.37 (m, 1H), 7.20- 7.17 (m, 1H), 4.98-4.94 (m, 1H),4.38-4.35 (m, 2H), 4.07- 4.03 (m, 2H), 3.92-3.71 (m, 4H), 3.88 (s, 3H),2.89-2.77 (m, 2H), 2.50-2.32 (m ,5H), 2.08-1.97 (m, 3H); m/z 445. CExample 71

¹H NMR (400 MHz, DMSO- d₆) δ 11.11 (s, 1H), 8.06 (s, 1H), 7.81 (s, 1H),7.44 (s, 1H), 7.40-7.37 (m, 1H), 7.20- 7.17 (m, 1H), 4.98-4.94 (m, 1H),4.37-4.35 (m, 2H), 4.07- 4.02 (m, 2H), 3.92-3.71 (m, 4H), 3.88 (s, 3H),2.88-2.77 (m, 2H), 2.50-2.32 (m ,5H), 2.08-1.97 (m, 3H); m/z 445. CExample 72

¹H NMR (400 MHz, DMSO- d₆) δ 11.10 (s, 1H), 7.48-7.36 (m, 1H), 7.29 (d,J = 8.0 Hz, 1H), 7.05-6.99 (m, 1H), 6.98- 6.87 (m, 1H), 4.37-4.24 (m,3H), 3.98-3.95 (m, 2H), 3.85- 3.71 (m, 2H), 3.54-3.44 (m, 2H), 2.93-2.71(m, 2H), 2.40- 2.33 (m, 3H), 2.15-1.93 (m, 5H), 1.87-1.83 (m, 2H); m/z379. C Example 73

¹H NMR (400 MHz, DMSO- d₆) δ 10.74 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H),7.45 (s, 1H), 7.24-7.17 (m, 1H), 7.15- 7.07 (m, 1H), 6.50 (s, 1H), 4.75(s, 2H), 4.48-4.40 (m, 1H), 4.04-4.00 (m, 2H), 3.84- 3.77 (m, 2H), 3.53(t, J = 12.0 Hz, 2H), 2.97-2.75 (m, 2H), 2.40-2.28 (m, 2H), 2.17- 2.09(m, 3H), 1.87-1.83 (m, 2H); m/z 365. C Example 74

¹H NMR (400 MHz, CDCl₃) δ 9.71-9.67 (m, 1H), 8.71- 8.64 (m, 1H),8.13-8.06 (m, 1H), 7.86-7.79 (m, 1H), 7.55- 7.47 (m, 1H), 4.63-4.40 (m,2H), 4.33-4.23 (m, 1H), 4.19- 4.12 (m, 2H), 4.04-3.81 (m, 2H), 3.59-3.52(m, 2H), 2.96- 2.82 (m, 2H), 2.49-2.35 (m, 2H), 2.23-2.04 (m, 3H), 2.00-1.92 (m, 2H); m/z 411. D Example 75

¹H NMR (400 MHz, DMSO- d₆) δ 9.77 (s, 1H), 8.62-8.52 (m, 1H), 7.97-7.88(m, 1H), 7.72-7.64 (m, 1H), 7.60- 7.49 (m, 1H), 4.49 (s, 2H), 4.48-4.38(m, 1H), 4.05- 3.95 (m, 2H), 3.88-3.74 (m, 2H), 3.51 (t, J = 11.2 Hz,2H), 3.00-2.78 (m, 2H), 2.69 (s, 3H), 2.20-2.03 (m, 5H), 2.00- 1.87 (m,2H); m/z 391. D Example 76

¹H NMR (400 MHz, CDCl₃) δ 9.64-9.55 (m, 1H), 8.61- 8.52 (m, 1H),8.11-8.04 (m, 1H), 7.54-7.45 (m, 1H), 7.09- 7.02 (m, 1H), 4.63-4.40 (m,2H), 4.31-4.21 (m, 1H), 4.20- 4.13 (m, 2H), 4.06 (s, 3H), 3.98-3.80 (m,2H), 3.57 (t, J = 12.0 Hz, 2H), 2.95-2.82 (m, 2H), 2.50-2.37 (m, 2H),2.24-2.03 (m, 3H), 2.00- 1.93 (m, 2H); m/z 407. E Example 77

¹H NMR (400 MHz, DMSO- d₆) δ 9.41 (s, 1H), 8.22 (s, 1H), 8.17 (d, J =8.4 Hz, 1H), 7.87-7.80 (m, 1H), 7.73- 7.61 (m, 1H), 4.50 (s, 2H),4.49-4.39 (m, 1H), 4.08 (s, 3H), 4.04-3.95 (m, 2H), 3.86- 3.76 (m, 2H),3.51 (t, J = 12.0 Hz, 2H), 3.02-2.79 (m, 2H), 2.15-2.02 (m, 5H), 2.01-1.89 (m, 2H); m/z 407. E Example 78

¹H NMR (400 MHz, DMSO- d₆) δ 9.69 (s, 1H), 8.69 (s, 1H), 8.21 (d, J =8.4 Hz, 1H), 7.93-7.84 (m, 1H), 7.74- 7.62 (m, 1H), 7.55-7.48 (m, 1H),5.98 (d, J = 17.6 Hz, 1H), 5.60 (d, J = 12.4 Hz, 1H), 4.50 (s, 2H),4.49-4.39 (m, 1H), 4.05-3.95 (m, 2H), 3.86-3.77 (m, 2H), 3.51 (t, J =12.0 Hz, 2H), 2.98-2.80 (m, 2H), 2.20-2.04 (m, 5H), 2.02-1.92 (m, 2H);m/z 403. F Example 79

¹H NMR (400 MHz, CDCl₃) δ 9.66-9.55 (m, 1H), 8.61- 8.52 (m, 1H),7.88-7.84 (m, 1H), 7.63-7.56 (m, 1H), 7.55- 7.48 (m, 1H), 4.62-4.40 (m,2H), 4.32-4.23 (m, 1H), 4.21- 4.07 (m, 2H), 4.04-3.82 (m, 2H), 3.56 (t,J = 12.0 Hz, 2H), 3.09 (q, J = 7.2 Hz, 2H), 2.96-2.82 (m, 2H), 2.49-2.36 (m, 2H), 2.23-2.04 (m, 3H), 2.00-1.92 (m, 2H), 1.41 (t, J = 7.2 Hz,3H); m/z 405. G Example 80

¹H NMR (400 MHz, DMSO- d₆) δ 9.60 (s, 1H), 8.41 (s, 1H), 8.13 (d, J =8.8 Hz, 1H), 7.92-7.83 (m, 1H), 7.72- 7.57 (m, 1H), 4.50 (s, 2H),4.49-4.39 (m, 1H), 4.06- 3.92 (m, 2H), 3.89-3.75 (m, 2H), 3.52 (t, J =12.0 Hz, 2H), 3.09 (q, J = 7.6 Hz, 2H), 3.00- 2.81 (m, 2H), 2.19-2.05(m, 5H), 2.04-1.89 (m, 2H), 1.33 (t, J = 7.6 Hz, 3H); m/z 405. G Example81

¹H NMR (400 MHz, DMSO- d₆) δ 9.78 (s, 1H), 8.55 (d, J = 6.0 Hz, 1H),7.97 (d, J = 6.4 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.67-7.56 (m, 1H),5.50- 5.41 (m, 1H), 4.99 (d, J = 5.6 Hz, 2H), 4.50 (s, 2H), 4.49- 4.39(m, 1H), 4.05-3.95 (m, 2H), 3.87-3.76 (m, 2H), 3.51 (t, J = 12.0 Hz,2H), 2.98- 2.82 (m, 2H), 2.14-2.02 (m, 5H), 2.00-1.88 (m, 2H); m/z 407.H Example 82

¹H NMR (400 MHz, DMSO- d₆) δ 9.67 (s, 1H), 8.51 (s, 1H), 8.15 (d, J =8.4 Hz, 1H), 7.91-7.83 (m, 1H), 7.72- 7.60 (m, 1H), 5.42 (s, 1H), 4.98(s, 2H), 4.49 (s, 2H), 4.48- 4.41 (m, 1H), 4.06-3.92 (m, 2H), 3.87-3.77(m, 2H), 3.51 (t, J = 12.0 Hz, 2H), 3.00- 2.81 (m, 2H), 2.18-2.02 (m,5H), 2.01-1.88 (m, 2H); m/z 407. H Example 83

¹H NMR (400 MHz, CDCl₃) δ 9.54-9.48 (m, 1H), 8.10- 7.96 (m, 2H),7.75-7.72 (m, 1H), 7.59-7.54 (m, 1H), 7.34- 7.32 (m, 1H), 4.63-4.44 (m,2H), 4.30-4.22 (m, 1H), 4.20- 4.12 (m, 2H), 4.07-3.79 (m, 2H), 4.00 (s,3H), 3.60- 3.54 (m, 2H), 2.94-2.83 (m, 2H), 2.65-2.52 (m, 3H), 2.51-2.36 (m, 2H), 2.22-2.04 (m, 3H), 1.97-1.94 (m, 2H); m/z 471. I Example84

¹H NMR (400 MHz, CDCl₃) δ 8.86-8.84 (m, 1H), 8.03 (s, 1H), 7.98-7.96 (m,1H), 7.78- 7.72 (m, 2H), 7.61-7.57 (m, 1H), 4.31-4.25 (m, 1H), 4.16-4.07 (m, 4H), 3.98 (s, 3H), 3.96-3.66 (m, 2H), 3.57 (t, J = 12.0 Hz,2H), 2.94-2.86 (m, 2H), 2.41-2.35 (m, 2H), 3.37 (s, 3H), 2.19-2.00 (m,3H), 1.97-1.93 (m, 2H); m/z 471. I Example 85

¹H NMR (400 MHz, DMSO- d₆) δ 9.39-9.36 (m, 1H), 8.34 (s, 1H), 8.14 (s,1H), 8.07 (s, 1H), 8.05-8.00 (m, 1H), 7.80- 7.75 (m, 1H), 4.49-4.46 (m,1H), 4.37 (s, 2H), 4.05-3.97 (m, 2H), 3.91 (s, 3H), 3.85- 3.79 (m, 2H),3.52 (t, J = 12.0 Hz, 2H), 3.02-2.85 (m, 2H), 2.16-1.93 (m, 7H); m/z475. I Example 86

¹H NMR (400 MHz, DMSO- d₆) δ 9.58-9.55 (m, 1H), 9.43 (s, 1H), 8.88-8.83(m, 1H), 8.77 (s, 1H), 8.76-8.74 (m, 1H), 8.25-8.21 (m, 1H), 8.20- 8.17(m, 1H), 7.94-7.89 (m, 1H), 4.53-4.50 (m, 1H), 4.39 (s, 2H), 4.05-3.97(m, 2H), 3.90-3.78 (m, 2H), 3.53 (t, J = 12.4 Hz, 2H), 3.02- 2.85 (m,2H), 2.86 (d, J = 5.2 Hz, 3H), 2.16-1.93 (m, 7H); m/z 529. I Example 87

¹H NMR (400 MHz, DMSO- d₆) δ 10.00 (s, 1H), 9.45 (s, 1H), 8.87 (s, 1H),8.79-8.76 (m, 1H), 8.71 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.08 (d, J =8.0 Hz, 1H), 7.94-7.89 (m, 1H), 7.75-7.66 (m, 1H), 4.58 (s, 2H),4.53-4.42 (m, 1H), 4.07-3.97 (m, 2H), 3.89- 3.79 (m, 2H), 3.56-3.50 (m,2H), 3.00-2.80 (m, 2H), 2.86 (s, 3H), 2.22-1.90 (m, 7H); m/z 411. IExample 88

¹H NMR (400 MHz, DMSO- d₆) δ 9.81 (s, 1H), 8.36 (s, 1H), 8.12-8.07 (m,1H), 7.90- 7.86 (m, 1H), 7.81-7.76 (m, 1H), 7.59-7.50 (m, 1H), 4.55 (s,2H), 4.48-4.43 (m, 1H), 4.03-4.00 (m, 2H), 3.91 (s, 3H), 3.85-3.80 (m,2H), 3.55- 3.49 (m, 2H), 2.96-2.82 (m, 2H), 2.20-2.02 (m, 5H), 1.99-1.91 (m, 2H); m/z 457. I Example 89

¹H NMR (400 MHz, DMSO- d₆) δ 9.76 (s, 1H), 8.36 (s, 1H), 8.13-8.05 (m,1H), 7.90- 7.87 (m, 1H), 7.81-7.76 (m, 1H), 7.58-7.50 (m, 1H), 5.10-5.06 (m, 1H), 4.54 (s, 2H), 4.11-4.05 (m, 2H), 3.98- 3.78 (m, 4H), 3.95(s, 3H), 2.98-2.78 (m, 2H), 2.42- 2.37 (m, 2H), 2.10-2.01 (m, 3H); m/z443. I Example 90

¹H NMR (400 MHz, CDCl₃) δ 9.72-9.65 (m, 1H), 7.92 (s, 1H), 7.85-7.64 (m,3H), 7.54- 7.46 (m, 1H), 4.65-4.47 (m, 2H), 4.37-4.23 (m, 1H), 4.21-4.15 (m, 2H), 4.07-3.82 (m, 2H), 3.89 (s, 3H), 3.63-3.54 (m, 2H),2.96-2.84 (m, 2H), 2.67 (s, 3H), 2.54-2.39 (m, 2H), 2.21-2.08 (m, 3H),2.01- 1.93 (m, 2H); m/z 471. I Example 91

¹H NMR (400 MHz, DMSO- d₆) δ 9.35 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H),8.07 (s, 1H), 8.06-8.00 (m, 1H), 7.80- 7.75 (m, 1H), 6.55-6.47 (m, 1H),4.50-4.43 (m, 1H), 4.22 (s, 2H), 4.02-3.98 (m, 2H), 3.91 (s, 3H),3.73-3.67 (m, 2H), 3.55-3.48 (m, 2H), 2.87- 2.79 (m, 2H), 2.55-2.53 (m,3H), 2.18-2.08 (m, 2H), 1.97- 1.91 (m, 2H); m/z 490. J Example 92

¹H NMR (400 MHz, CDCl₃) δ 9.84 (s, 1H), 9.29 (s, 1H), 8.54- 8.51 (m,1H), 8.27 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 8.12- 8.05 (m, 1H), 7.90(d, J = 8.4 Hz, 1H), 7.80-7.75 (m, 1H), 7.61 (d, J = 7.2 Hz, 1H),4.61-4.50 (m, 1H), 4.40 (s, 2H), 4.34-4.27 (m, 1H), 4.19- 4.15 (m, 2H),3.90-3.87 (m, 2H), 3.62-3.55 (m, 2H), 3.08 (d, J = 5.2 Hz, 3H), 2.90-2.87 (m, 2H), 2.80 (d, J = 4.4 Hz, 3H), 2.50-2.40 (m, 2H), 2.04-1.93 (m,2H); m/z 526. J Example 93

¹H NMR (400 MHz, DMSO- d₆) δ 9.87 (s, 1H), 8.38 (s, 1H), 8.16-8.13 (m,1H), 8.11 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.86-7.80 (m, 1H), 7.56 (d,J = 8.0 Hz, 1H), 6.65- 6.53 (m, 1H), 4.52-4.42 (m, 3H), 4.05-3.98 (m,2H), 3.92 (s, 3H), 3.73-3.67 (m, 2H), 3.55-3.48 (m, 2H), 2.87- 2.79 (m,2H), 2.55-2.53 (m, 3H), 2.18-2.08 (m, 2H), 1.97- 1.91 (m, 2H); m/z 472.J Example 94

¹H NMR (400 MHz, CDCl₃) δ 9.65 (s, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.83(d, J = 8.4 Hz, 1H), 7.75-7.70 (m, 1H), 7.54 (d, J = 7.2 Hz, 1H), 4.52-4.44 (m, 1H), 4.34 (s, 2H), 4.30-4.26 (m, 1H), 4.21- 4.13 (m, 2H),3.89-3.86 (m, 2H), 3.60-2.64 (m, 2H), 2.88- 2.86 (m, 2H), 2.80-2.77 (m,6H), 2.48-2.38 (m, 2H), 1.97- 1.94 (m, 2H); m/z 489. J Example 95

¹H NMR (400 MHz, CDCl₃) δ 7.57-7.23 (m, 5H), 7.22- 6.83 (m, 3H),6.75-6.57 (m, 1H), 4.48 (s, 2H), 4.41-4.24 (m, 1H), 4.07-3.83 (m, 2H),3.75-3.50 (m, 4H), 2.85- 2.65 (m, 2H), 2.59 (s, 3H), 2.17-1.92 (m, 2H),1.90- 1.71 (m, 2H); m/z 433. J Example 96

¹H NMR (400 MHz, DMSO- d₆) δ 9.89-9.80 (m, 1H), 8.40 (s, 1H), 8.34 (s,1H), 7.99 (d, J = 8.0 Hz, 1H), 7.93-7.82 (m, 1H), 7.71-7.59 (m, 1H),4.55 (s, 2H), 4.54-4.41 (m, 1H), 4.09 (s, 3H), 4.06-3.98 (m, 2H),3.88-3.77 (m, 2H), 3.52 (t, J = 12.0 Hz, 2H), 3.01- 2.80 (m, 2H),2.19-2.02 (m, 5H), 2.01-1.88 (m, 2H); m/z 482. K Example 97

¹H NMR (400 MHz, DMSO- d₆) δ 9.83-9.76 (m, 1H), 8.50 (s, 1H), 8.11 (s,1H), 7.93 (d, J = 8.0 Hz, 1H), 7.86-7.79 (m, 1H), 7.65-7.54 (m, 1H),7.58 (t, J = 54.0 Hz, 1H), 4.54 (s, 2H), 4.52-4.41 (m, 1H), 4.07-3.93(m, 2H), 3.97 (s, 3H), 3.88-3.77 (m, 2H), 3.52 (t, J = 12.0 Hz, 2H),3.01- 2.81 (m, 2H), 2.20-2.01 (m, 5H), 2.00-1.88 (m, 2H); m/z 507. KExample 98

¹H NMR (400 MHz, DMSO- d₆) δ 9.81 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H),8.13 (t, J = 54.0 Hz, 1H), 8.04-7.93 (m, 1H), 7.90-7.82 (m, 1H), 7.69-7.56 (m, 1H), 4.54 (s, 2H), 4.53-4.41 (m, 1H), 4.06 (s, 3H), 4.05-4.00(m, 2H), 3.89- 3.73 (m, 2H), 3.52 (t, J = 12.0 Hz, 2H), 3.02-2.81 (m,2H), 2.23-2.01 (m, 5H), 2.00- 1.88 (m, 2H); m/z 507. K Example 99

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.27 (m, 1H), 7.25- 7.12 (m, 2H),6.71-6.59 (m, 1H), 4.60-4.38 (m, 4H), 4.26- 4.07 (m, 3H), 3.96-3.75 (m,2H), 3.74-3.67 (m, 2H), 3.60- 3.48 (m, 2H), 2.86-2.76 (m, 2H), 2.40-2.29(m, 2H), 2.20- 2.10 (m, 3H), 1.99-1.82 (m, 2H); m/z 395. L Example 100

¹H NMR (400 MHz, CDCl₃) δ 8.83-8.72 (m, 1H), 7.92- 7.78 (m, 1H), 7.57(d, J = 6.4 Hz, 1H), 7.45-7.34 (m, 2H), 4.62-4.40 (m, 2H), 4.31- 4.23(m, 1H), 4.21-4.12 (m, 2H), 4.04-3.82 (m, 2H), 3.58 (t, J = 12.0 Hz,2H), 2.95- 2.84 (m, 2H), 2.49-2.38 (m, 2H), 2.24-2.05 (m, 3H), 2.01-1.91 (m, 2H); m/z 393. L Example 101

¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H),7.40-7.17 (m, 3H), 4.90-4.87 (m, 2H), 4.57- 4.42 (m, 2H), 4.27-4.08 (m,3H), 4.00-3.75 (m, 4H), 3.91 (s, 3H), 3.57 (t, J = 12.0 Hz, 2H),2.90-2.76 (m, 2H), 2.43- 2.25 (m, 2H), 2.20-2.11 (m, 3H), 1.95-1.85 (m,2H); m/z 475. L Example 102

¹H NMR (400 MHz, CDCl₃) δ 7.44-7.42 (m, 1H), 7.35- 7.31 (m, 2H),7.23-7.17 (m, 1H), 4.78-4.76 (m, 2H), 4.57- 4.45 (m, 2H), 4.25-4.13 (m,3H), 3.98-3.79 (m, 7H), 3.55 (t, J = 12.0 Hz, 2H), 2.87- 2.80 (m, 2H),2.43-2.28 (m, 2H), 2.21-2.10 (m, 6H), 1.97- 1.76 (m, 2H); m/z 489. LExample 103

¹H NMR (400 MHz, DMSO- d₆) δ 7.92 (d, J = 2.8 Hz, 1H), 7.37-7.24 (m,4H), 6.58- 6.52 (m, 1H), 6.48-6.41 (m, 1H), 4.83 (s, 2H), 4.46 (s, 2H),4.42-4.33 (m, 1H), 4.30- 3.94 (m, 2H), 3.85 (s, 2H), 3.83-3.73 (m, 4H),3.55- 3.40 (m, 2H), 2.92-2.77 (m, 2H), 2.76 (d, J = 5.2 Hz, 3H),2.14-1.99 (m ,5H), 1.92- 1.82 (m, 2H); m/z 501. L Example 104

¹H NMR (400 MHz, DMSO- d₆) δ 8.04 (d, J = 2.4 Hz, 1H), 7.49-7.45 (m,1H), 7.39- 7.24 (m, 3H), 6.65 (d, J = 9.2 Hz, 1H), 4.86 (s, 2H), 4.47(s, 2H), 4.43-7.31 (m, 1H), 4.06- 3.95 (m, 2H), 3.89-3.84 (m, 2H),3.83-3.72 (m, 2H), 3.46 (d, J = 11.6 Hz, 2H), 3.02 (s, 6H), 2.94-2.75(m, 2H), 2.12- 2.01 (m, 5H), 1.93-1.82 (m, 2H); m/z 515. L Example 105

¹H NMR (400 MHz, CDCl₃) δ 8.64 (s, 1H), 8.26 (d, J = 8.8 Hz, 2H),8.00-7.91 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.39- 7.33 (m, 2H),4.97-4.93 (m, 2H), 4.60-4.48 (m, 2H), 4.25- 4.10 (m, 3H), 4.02-3.82 (m,4H), 3.56 (t, J = 12.0 Hz, 2H), 3.05 (d, J = 5.2 Hz, 3H), 2.89- 2.80 (m,2H), 2.45-2.30 (m, 2H), 2.22-2.14 (m, 3H), 1.97- 1.87 (m, 2H); m/z 529.L Example 106

¹H NMR (400 MHz, DMSO- d₆) δ 8.09 (s, 1H), 7.84 (s, 1H), 7.80-7.71 (m,2H), 7.55- 7.41 (m, 2H), 6.66 (s, 1H), 4.50-4.47 (m, 2H), 3.87 (s, 3H),3.82-3.72 (m, 5H), 2.88- 2.73 (m, 2H), 2.11-2.05 (m, 3H); m/z 375. MExample 107

¹H NMR (400 MHz, DMSO- d₆) δ 8.46-8.40 (m, 1H), 8.17 (s, 1H), 7.96 (s,1H), 7.92 (s, 1H), 7.81-7.69 (m, 1H), 7.56 (d, J = 8.4 Hz, 1H), 4.57-4.51 (m, 2H), 3.88 (s, 3H), 3.83-3.72 (m, 5H), 2.90- 2.74 (m, 2H),2.11-2.06 (m, 3H); m/z 376. M Example 108

¹H NMR (400 MHz, DMSO- d₆) δ 8.42-8.36 (m, 1H), 8.18 (s, 1H), 7.91-7.73(m, 3H), 7.53 (d, J = 8.4 Hz, 1H), 4.54- 4.49 (m, 2H), 3.87 (s, 3H),3.85-3.75 (m, 5H), 2.92- 2.76 (m, 2H), 2.13-2.04 (m, 3H); m/z 376. MExample 109

¹H NMR (400 MHz, DMSO- d₆) δ 7.88-7.76 (m, 1H), 7.64 (d, J = 7.6 Hz,1H), 7.60- 7.47 (m, 1H), 7.26-7.18 (m, 1H), 7.17-7.09 (m, 1H), 6.69 (s,1H), 4.54-4.46 (m, 2H), 4.45-4.34 (m, 1H), 4.08- 3.94 (m, 2H), 3.80-3.76(m, 2H), 3.49 (t, J = 12.0 Hz, 2H), 2.98-2.77 (m, 2H), 2.14- 2.02 (m,5H), 1.96-1.82 (m, 2H); m/z 365. M Example 110

H NMR (400 MHz, DMSO- d₆) δ 7.85-7.75 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H),7.38- 7.26 (m, 1H), 7.25-7.18 (m, 1H), 7.17-7.09 (m, 1H), 4.57- 4.45 (m,2H), 4.44-4.30 (m, 1H), 4.02-3.9 (m, 2H), 3.86- 3.72 (m, 2H), 3.49 (t, J= 12.0 Hz, 2H), 2.95-2.73 (m, 2H), 2.33 (s, 3H), 2.16-1.99 (m, 5H),1.93-1.81 (m, 2H); m/z 379. M Example 111

¹H NMR (400 MHz, DMSO- d₆) δ 9.46 (t, J = 0.9 Hz, 1H), 7.61 (dt, J =8.5, 1.0 Hz, 1H), 7.57-7.47 (m, 1H), 7.22- 7.04 (m, 1H), 6.69-6.57 (m,1H), 4.51 (s, 2H), 4.43 (d, J = 4.2 Hz, 1H), 4.16-4.08 (m, 1H),4.08-3.97 (m, 2H), 3.87- 3.75 (m, 2H), 3.61-3.40 (m, 6H), 3.29 (s, 3H),2.98- 2.77 (m, 2H), 2.18-1.97 (m, 7H), 1.93 (d, J = 9.3 Hz, 2H); m/z476.3. N Example 112

¹H NMR (400 MHz, DMSO- d₆) δ 9.46 (t, J = 0.9 Hz, 1H), 7.61 (dt, J =8.5, 1.0 Hz, 1H), 7.57-7.47 (m, 1H), 7.22- 7.04 (m, 1H), 6.69-6.57 (m,1H), 4.51 (s, 2H), 4.43 (d, J = 4.2 Hz, 1H), 4.16-4.08 (m, 1H),4.08-3.97 (m, 2H), 3.87- 3.75 (m, 2H), 3.61-3.40 (m, 6H), 3.29 (s, 3H),2.98- 2.77 (m, 2H), 2.18-1.97 (m, 7H), 1.93 (d, J = 9.3 Hz, 2H); m/z476.4. N Example 113

¹H NMR (400 MHz, DMSO- d₆) δ 9.42 (t, J = 0.8 Hz, 1H), 7.60 (dt, J =8.4, 0.9 Hz, 1H), 7.51 (ddd, J = 8.9, 6.9, 2.1 Hz, 1H), 7.20-7.03 (m,1H), 6.60 (s, 1H), 4.49 (d, J = 1.3 Hz, 2H), 4.43 (td, J = 11.3, 9.6,5.7 Hz, 1H), 4.30-4.20 (m, 1H), 4.06-3.97 (m, 2H), 3.82 (dt, J = 17.8,6.1 Hz, 2H), 3.59-3.47 (m, 3H), 3.37- 3.32 (m, 1H), 2.88 (dt, J = 48.5,5.8 Hz, 1H), 2.14-1.90 (m, 10H), 1.70 (d, J = 5.1 Hz, 1H), 1.20 (d, J =6.2 Hz, 3H); m/z 460.2. N Example 114

¹H NMR (400 MHz, DMSO- d₆) δ 9.42 (t, J = 0.8 Hz, 1H), 7.60 (dt, J =8.4, 0.9 Hz, 1H), 7.51 (ddd, J = 8.9, 6.9, 2.1 Hz, 1H), 7.20-7.03 (m,1H), 6.60 (s, 1H), 4.49 (d, J = 1.3 Hz, 2H), 4.43 (td, J = 11.3, 9.6,5.7 Hz, 1H), 4.30-4.20 (m, 1H), 4.06-3.97 (m, 2H), 3.82 (dt, J = 17.8,6.1 Hz, 2H), 3.59-3.47 (m, 3H), 3.37- 3.32 (m, 1H), 2.88 (dt, J = 48.5,5.8 Hz, 2H), 2.14-1.90 (m, 10H), 1.70 (d, J = 5.1 Hz, 1H), 1.20 (d, J =6.2 Hz, 3H); m/z 460.2. N Example 115

¹H NMR (400 MHz, DMSO- d₆) δ 9.48 (t, J = 0.9 Hz, 1H), 8.53 (s, 1H),7.68-7.58 (m, 1H), 7.55 (ddd, J = 9.0, 7.0, 2.3 Hz, 1H), 7.23-7.10 (m,1H), 6.70 (s, 1H), 4.51 (s, 2H), 4.43 (d, J = 4.0 Hz, 1H), 4.04-3.98 (m,2H), 3.83- 3.68 (m, 4H), 3.56-3.46 (m, 4H), 2.97-2.81 (m, 2H), 2.31-2.08 (m, 7H), 1.96-1.90 (m, 2H); m/z 464.2. N Example 116

¹H NMR (400 MHz, DMSO- d₆) δ 9.46 (t, J = 0.8 Hz, 1H), 7.60 (dt, J =8.5, 1.0 Hz, 1H), 7.53 (ddd, J = 8.8, 6.9, 2.1 Hz, 1H), 7.21-7.04 (m,1H), 6.64 (d, J = 0.9 Hz, 1H), 4.50 (s, 2H), 4.47-4.39 (m, 1H),4.07-3.94 (m, 2H), 3.85- 3.72 (m, 3H), 3.66 (t, J = 9.2 Hz, 1H),3.57-3.46 (m, 2H), 3.41 (td, J = 10.1, 6.8 Hz, 1H), 3.19 (dd, J = 10.0,8.2 Hz, 1H), 2.94 (t, J = 5.8 Hz, 1H), 2.81 (t, J = 8.2 Hz, 2H), 2.23(s, 6H), 2.21-1.99 (m, 6H), 1.92 (dd, J = 11.9, 6.4 Hz, 2H), 1.89-1.81(m, 1H); m/z 489.3. N Example 117

Not Determined; m/z 496.2. N Example 118

¹H NMR (400 MHz, DMSO- d₆) δ 9.43 (d, J = 0.8 Hz, 1H), 7.59 (dt, J =8.6, 1.0 Hz, 1H), 7.56-7.47 (m, 1H), 7.20- 7.04 (m, 1H), 6.59 (d, J =0.9 Hz, 1H), 4.50 (d, J = 2.2 Hz, 2H), 4.47-4.38 (m, 1H), 4.01 (dt, J =9.5, 4.5 Hz, 2H), 3.81 (dt, J = 15.2, 5.8 Hz, 2H), 3.69 (dd, J = 10.1,7.2 Hz, 1H), 3.59 (dd, J = 3.7, 2.3 Hz, 1H), 3.55-3.49 (m, 2H), 3.47-3.41 (m, 1H), 3.01 (dd, J = 10.1, 7.5 Hz, 1H), 2.98-2.78 (m, 2H),2.43-2.33 (m, 1H), 2.21-2.01 (m, 6H), 1.93 (d, J = 12.6 Hz, 2H), 1.63(dq, J = 12.0, 8.2 Hz, 1H), 1.11 (d, J = 6.6 Hz, 3H); m/z 460.3. NExample 119

¹H NMR (400 MHz, DMSO- d₆) δ 9.49-9.37 (m, 1H), 7.59 (dt, J = 8.6, 1.0Hz, 1H), 7.51 (ddd, J = 8.8, 6.9, 2.0 Hz, 1H), 7.17-7.05 (m, 1H), 6.59(d, J = 0.9 Hz, 1H), 4.50 (d, J = 2.1 Hz, 2H), 4.43 (q, J = 5.6, 4.2 Hz,1H), 4.04- 3.97 (m, 2H), 3.85-3.76 (m, 2H), 3.72-3.65 (m, 1H), 3.58(ddd, J = 4.5, 3.8, 1.3 Hz, 1H), 3.55-3.48 (m, 2H), 3.47- 3.41 (m, 1H),3.06-2.97 (m, 1H), 2.97-2.77 (m, 2H), 2.45-2.33 (m, 1H), 2.16- 2.00 (m,6H), 1.93 (d, J = 12.2 Hz, 2H), 1.69-1.57 (m, 1H), 1.11 (d, J = 6.6 Hz,3H); m/z 460.3. N Example 120

¹H NMR (400 MHz, DMSO- d₆, 34/36 H) δ 9.51-9.41 (m, 1H), 7.61 (dt, J =8.5, 1.0 Hz, 1H), 7.53 (ddd, J = 8.8, 6.9, 2.1 Hz, 1H), 7.22-7.07 (m,1H), 6.64 (d, J = 0.9 Hz, 1H), 4.51 (d, J = 1.7 Hz, 2H), 4.48- 4.37 (m,1H), 4.08-3.96 (m, 2H), 3.88-3.71 (m, 3H), 3.65-3.45 (m, 6H), 3.10 (s,3H), 2.98-2.78 (m, 5H), 2.10 (s, 5H), 1.97-1.88 (m, 2H); m/z 517.3. NExample 121

¹H NMR (400 MHz, DMSO- d₆) δ 9.43 (t, J = 0.9 Hz, 1H), 7.59 (dt, J =8.5, 1.0 Hz, 1H), 7.55-7.48 (m, 1H), 7.17- 7.06 (m, 1H), 6.62-6.55 (m,1H), 4.50 (s, 2H), 4.46-4.39 (m, 1H), 4.01 (d, J = 11.5 Hz, 2H),3.86-3.78 (m, 2H), 3.57- 3.51 (m, 4H), 2.94 (t, J = 5.7 Hz, 2H),2.14-2.06 (m, 5H), 1.96-1.91 (m, 2H), 1.13 (s, 6H), 1.06-1.01 (m, 2H),0.90 (dd, J = 4.9, 2.0 Hz, 2H); m/z 474.3. N Example 122

¹H NMR (400 MHz, DMSO- d₆) δ 9.51 (t, J = 0.8 Hz, 1H), 7.66 (dt, J =8.5, 1.0 Hz, 1H), 7.58 (ddd, J = 8.3, 6.9, 2.5 Hz, 1H), 7.27-7.11 (m,1H), 6.76 (d, J = 1.0 Hz, 1H), 5.61- 5.48 (m, 1H), 5.48-5.34 (m, 1H),4.51 (s, 2H), 4.44 (dt, J = 8.3, 4.2 Hz, 1H), 4.07- 3.97 (m, 2H),3.97-3.87 (m, 2H), 3.85-3.78 (m, 2H), 3.73-3.63 (m, 2H), 3.57- 3.46 (m,2H), 2.98-2.77 (m, 2H), 2.16-2.00 (m, 5H), 1.93 (d, J = 11.5 Hz, 2H);m/z 482.2. N Example 123

Not Determined; m/z 474.3. N Example 124

¹H NMR (400 MHz, DMSO- d₆) δ 9.49 (t, J = 0.8 Hz, 1H), 7.69-7.59 (m,1H), 7.55 (ddd, J = 8.9, 7.0, 2.3 Hz, 1H), 7.24-6.96 (m, 1H), 6.65 (d, J= 0.9 Hz, 1H), 6.08 (s, 2H), 4.51 (d, J = 1.7 Hz, 2H), 4.48-4.38 (m,1H), 4.28 (s, 4H), 4.07-3.97 (m, 2H), 3.87- 3.77 (m, 2H), 3.57-3.50 (m,2H), 2.98-2.77 (m, 2H), 2.16-2.00 (m, 5H), 1.93 (d, J = 9.4 Hz, 2H); m/z444.2. N Eample 125

Not Determined; m/z 482.2. N Example 126

Not Determined; m/z 471.2. N Example 127

¹H NMR (400 MHz, DMSO- d₆) δ 9.50 (d, J = 1.0 Hz, 1H), 7.70-7.63 (m,1H), 7.63- 7.51 (m, 1H), 7.31-7.17 (m, 1H), 7.02 (d, J = 0.9 Hz, 1H),4.52 (d, J = 2.7 Hz, 2H), 4.44 (dd, J = 11.3, 4.1 Hz, 1H), 4.07-3.95 (m,2H), 3.88- 3.75 (m, 2H), 3.53 (ddd, J = 8.9, 7.4, 3.4 Hz, 6H), 3.01-2.77 (m, 2H), 2.46 (t, J = 5.0 Hz, 4H), 2.24 (s, 3H), 2.15- 2.00 (m,5H), 1.93 (d, J = 11.4 Hz, 2H); m/z 475.3. N Example 128

¹H NMR (400 MHz, DMSO- d₆) δ 9.47 (d, J = 0.8 Hz, 1H), 7.76-7.48 (m,2H), 7.19 (ddd, J = 26.4, 7.1, 1.2 Hz, 1H), 6.99 (d, J = 1.0 Hz, 1H),4.51 (d, J = 2.5 Hz, 2H), 4.43 (td, J = 11.2, 5.4 Hz, 1H), 4.09-3.95 (m,2H), 3.81 (dt, J = 14.5, 5.8 Hz, 2H), 3.66- 3.45 (m, 6H), 3.01-2.77 (m,2H), 2.22-1.98 (m, 5H), 1.98- 1.85 (m, 2H), 1.61 (d, J = 7.6 Hz, 6H);m/z 460.3. N Example 129

¹H NMR (400 MHz, DMSO- d₆) δ 9.44 (t, J = 0.8 Hz, 1H), 7.60 (dt, J =8.5, 1.0 Hz, 1H), 7.52 (ddd, J = 8.8, 6.9, 2.1 Hz, 1H), 7.12 (ddd, J =26.7, 6.9, 1.2 Hz, 1H), 6.67-6.47 (m, 1H), 4.50 (s, 2H), 4.47- 4.35 (m,1H), 4.10-3.92 (m, 2H), 3.81 (dt, J = 15.2, 5.8 Hz, 2H), 3.57-3.41 (m,6H), 2.88 (dt, J = 48.6, 5.9 Hz, 2H), 2.19-2.04 (m, 4H), 2.02- 1.96 (m,5H), 1.97-1.89 (m, 2H); m/z 446.2. N Example 130

¹H NMR (400 MHz, DMSO- d₆) δ 9.53 (d, J = 0.9 Hz, 1H), 7.73-7.65 (m,1H), 7.65- 7.56 (m, 1H), 7.39-7.19 (m, 1H), 7.04 (d, J = 0.9 Hz, 1H),4.52 (d, J = 3.2 Hz, 2H), 4.49- 4.36 (m, 1H), 4.09-3.93 (m, 2H),3.88-3.72 (m, 6H), 3.52 (q, J = 6.8, 5.2 Hz, 6H), 2.99-2.77 (m, 2H),2.16- 1.99 (m, 5H), 1.93 (d, J = 11.0 Hz, 2H); m/z 462.2. N Example 131

¹H NMR (400 MHz, DMSO- d₆) δ 8.93 (dd, J = 4.1, 1.7 Hz, 1H), 8.87 (ddt,J = 9.0, 2.5, 1.2 Hz, 1H), 8.04 (dt, J = 8.5, 1.0 Hz, 1H), 7.83 (ddd, J= 8.4, 7.1, 3.2 Hz, 1H), 7.61-7.53 (m, 2H), 4.49 (s, 2H), 4.44 (ddd, J =11.3, 7.4, 4.0 Hz, 1H), 4.05- 3.96 (m, 2H), 3.82 (dt, J = 13.9, 5.8 Hz,2H), 3.59-3.46 (m, 2H), 2.95 (t, J = 6.9 Hz, 1H), 2.89-2.77 (m, 1H),2.20- 206 (m, 4H), 2.00 (s, 1H), 1.97-1.88 (m, 2H); m/z 377. O Example132

¹H NMR (400 MHz, DMSO- d₆) δ 8.67 (d, J = 2.8 Hz, 1H), 7.54 (d, J = 8.6Hz, 1H), 7.30 (ddd, J = 8.5, 6.9, 3.4 Hz, 1H), 7.12-7.01 (m, 1H), 4.71(s, 2H), 4.39 (tt, J = 11.5, 4.2 Hz, 1H), 4.23 (s, 3H), 4.03 (dd, J =11.4, 4.3 Hz, 2H), 3.85-3.74 (m, 2H), 3.53 (td, J = 11.9, 1.8 Hz, 2H),2.94- 2.74 (m, 2H), 2.29-2.15 (m, 2H), 2.15-2.08 (m, 3H), 1.89 (dd, J =12.2, 4.9 Hz, 2H); m/z 380. O Example 133

¹H NMR (400 MHz, DMSO- d₆) δ 8.36-8.28 (m, 1H), 8.02-7.91 (m, 2H), 7.62-7.43 (m, 4H), 4.41 (s, 3H), 4.01 (dd, J = 10.6, 4.8 Hz, 2H), 3.87-3.75(m, 2H), 3.57- 3.46 (m, 2H), 2.99-2.79 (m, 2H), 2.20-2.03 (m, 4H),2.00-1.88 (m, 3H); m/z 376. O Example 134

¹H NMR (400 MHz, DMSO- d₆) δ 11.09 (d, J = 10.7 Hz, 1H), 7.69-7.60 (m,1H), 7.57 (d, J = 8.2 Hz, 1H), 7.41- 7.28 (m, 2H), 6.42 (ddd, J = 2.9,1.9, 0.9 Hz, 1H), 4.69 (d, J = 8.4 Hz, 2H), 4.33 (ddt, J = 11.3, 7.3,4.1 Hz, 1H), 4.05- 3.94 (m, 2H), 3.78 (dt, J = 19.0, 5.9 Hz, 2H),3.57-3.43 (m, 2H), 2.91-2.71 (m, 2H), 2.18-2.05 (m, 5H), 1.85 (d, J =12.9 Hz, 2H); m/z 365. O Example 135

¹H NMR (400 MHz, DMSO- d₆) δ 8.77-8.63 (m, 1H), 8.17-7.99 (m, 1H), 7.88-7.63 (m, 1H), 7.50-7.34 (m, 2H), 4.66 (d, J = 4.4 Hz, 2H), 4.41 (td, J =11.3, 5.6 Hz, 1H), 4.07-3.97 (m, 2H), 3.80 (dt, J = 13.7, 5.8 Hz, 2H),3.58-3.46 (m, 2H), 2.91- 2.70 (m, 2H), 2.22-2.07 (m, 5H), 1.91 (d, J =13.3 Hz, 2H); m/z 382. O Example 136

¹H NMR (400 MHz, DMSO- d₆) δ 8.95 (dd, J = 4.5, 2.4 Hz, 1H), 8.61 (dt, J= 8.7, 2.0 Hz, 1H), 8.11-8.03 (m, 1H), 7.79 (ddd, J = 8.4, 6.8, 1.4 Hz,1H), 7.65 (dddd, J = 8.3, 6.8, 2.4, 1.3 Hz, 1H), 7.61-7.38 (m, 1H), 4.56(d, J = 5.2 Hz, 2H), 4.47 (ddt, J = 11.3, 7.3, 4.1 Hz, 1H), 4.10-3.95(m, 2H), 3.82 (dt, J = 11.9, 5.8 Hz, 2H), 3.58-3.47 (m, 2H), 3.01-2.79(m, 2H), 2.20- 2.05 (m, 4H), 2.01 (s, 1H), 1.95 (td, J = 6.1, 3.7 Hz,2H); m/z 377. O Example 137

¹H NMR (400 MHz, DMSO- d₆) δ 11.21 (d, J = 2.9 Hz, 1H), 7.45-7.34 (m,2H), 7.01 (ddd, J = 11.2, 8.8, 3.1 Hz, 1H), 6.71-6.58 (m, 1H), 4.39 (d,J = 2.1 Hz, 3H), 4.06- 3.96 (m, 2H), 3.86-3.74 (m, 2H), 3.57-3.45 (m,2H), 2.97- 2.75 (m, 2H), 2.17-2.04 (m, 4H), 1.99 (s, 1H), 1.96- 1.86 (m,2H); m/z 383. O Example 138

¹H NMR (400 MHz, DMSO- d₆) δ 11.30 (d, J = 5.6 Hz, 1H), 8.24 (dd, J =8.0, 1.3 Hz, 1H), 7.74-7.60 (m, 1H), 7.54 (td, J = 7.7, 1.8 Hz, 1H),7.17 (dt, J = 7.3, 5.1 Hz, 1H), 6.93 (t, J = 8.1 Hz, 1H), 4.47- 4.34 (m,3H), 3.99 (dd, J = 10.4, 4.7 Hz, 2H), 3.79 (dt, J = 12.0, 5.7 Hz, 2H),3.50 (td, J = 12.0, 2.3 Hz, 2H), 2.96- 2.76 (m, 2H), 2.12-2.05 (m, 3H),2.00 (s, 1H), 1.94-1.85 (m, 3H); m/z 393. O Example 139

¹H NMR (400 MHz, DMSO- d₆) δ 7.12 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 8.0Hz, 1H), 7.02- 6.96 (m, 1H), 4.34 (d, J = 3.3 Hz, 2H), 3.96 (d, J = 12.3Hz, 2H), 3.76 (dt, J = 16.8, 5.8 Hz, 2H), 3.47 (tt, J = 12.0, 2.2 Hz,2H), 2.87 (dd, J = 10.0, 4.3 Hz, 1H), 2.81-2.60 (m, 5H), 2.08 (s, 2H),2.06- 1.98 (m, 3H), 1.84 (dd, J = 12.8, 5.2 Hz, 2H), 1.78-1.61 (m, 5H);m/z 380. O Example 140

¹H NMR (400 MHz, DMSO- d₆) δ 13.09 (s, 1H), 8.54 (d, J = 6.2 Hz, 1H),7.49 (d, J = 8.3 Hz, 1H), 7.47-7.37 (m, 1H), 7.14 (ddd, J = 18.2, 7.1,0.8 Hz, 1H), 4.71 (s, 2H), 4.41 (ddd, J = 11.3, 8.9, 4.3 Hz, 1H),4.08-3.98 (m, 2H), 3.85- 2.74 (m, 2H), 3.59-3.47 (m, 2H), 2.96-2.76 (m,2H), 2.25-2.03 (m, 5H), 1.92 (d, J = 13.0 Hz, 2H); m/z 366. O Example141

¹H NMR (400 MHz, DMSO- d₆) δ 10.74 (s, 1H), 7.54 (d, J = 7.7 Hz, 1H),7.45 (t, J = 2.8 Hz, 1H), 7.26-7.15 (m, 1H), 7.11 (td, J = 7.6, 1.4 Hz,1H), 6.50 (dd, J = 3.1, 2.1 Hz, 1H), 4.75 (d, J = 3.2 Hz, 2H), 4.41(ddt, J = 11.6, 7.6, 4.0 Hz, 1H), 4.10-3.97 (m, 2H), 3.81 (dt, J = 15.5,5.8 Hz, 2H), 3.60-3.44 (m, 2H), 2.97- 2.74 (m, 2H), 2.37 (tq, J = 12.2,6.1, 5.5 Hz, 2H), 2.13 (d, J = 5.2 Hz, 3H), 1.87 (t, J = 8.3 Hz, 2H);m/z 365. O Example 142

¹H NMR (400 MHz, DMSO- d₆) δ 8.84 (dd, J = 12.2, 2.3 Hz, 1H), 8.63 (d, J= 2.1 Hz, 1H), 7.95-7.75 (m, 1H), 4.64 (s, 2H), 4.37 (ddq, J = 11.2,7.8, 4.0 Hz, 1H), 4.03 (dd, J = 10.6, 4.3 Hz, 2H), 3.78 (dt, J = 15.3,5.7 Hz, 2H), 3.51 (t, J = 11.7 Hz, 2H), 2.92-2.71 (m, 2H), 2.20-2.04 (m,6H), 1.94-1.84 (m, 2H); m/z 434. O Example 143

¹H NMR (400 MHz, DMSO- d₆) δ 9.59 (d, J = 4.5 Hz, 1H), 7.73 (ddd, J =8.5, 7.2, 3.6 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.28-7.10 (m, 1H), 6.82(s, 2H), 4.55 (s, 2H), 4.43 (tq, J = 11.4, 4.2 Hz, 1H), 4.01 (dd, J =10.7, 4.7 Hz, 2H), 3.81 (dt, J = 12.1, 5.8 Hz, 2H), 3.51 (tt, J = 11.7,2.1 Hz, 2H), 2.94- 2.74 (m, 2H), 2.18-2.00 (m, 5H), 1.98-1.87 (m, 2H);m/z 393. P Example 144

¹H NMR (400 MHz, DMSO- d₆) δ 9.81 (d, J = 1.0 Hz, 1H), 85.4 (d, J = 5.6Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.92- 7.80 (m, 2H), 7.73-7.59 (m,1H), 4.57-4.40 (m, 3H), 4.05- 3.96 (m, 2H), 3.83 (dt, J = 12.0, 5.8 Hz,2H), 3.58-3.46 (m, 2H), 3.02-2.80 (m, 2H), 2.20-2.05 (m, 4H), 2.01 (s,1H), 1.96 (t, J = 8.3 Hz, 2H); m/z 377. P Example 145

¹H NMR (400 MHz, DMSO- d₆) δ 7.81-7.61 (m, 5H), 7.10-7.01 (m, 2H), 5.19-5.13 (m, 2H), 4.75 (s, 2H), 4.42 (td, J = 11.1, 5.5 Hz, 1H), 4.02 (d, J= 11.7 Hz, 2H), 3.85-3.74 (m, 2H), 3.79 (s, 3H), 3.57-3.47 (m, 2H),2.95-2.75 (m, 2H), 2.18- 2.05 (m, 4H), 1.91 (d, J = 13.0 Hz, 3H); m/z487. Q Example 146

¹H NMR (400 MHz, DMSO- d₆) δ 8.14 (d, J = 1.7 Hz, 1H), 7.76-7.60 (m,4H), 5.06- 5.00 (m, 2H), 4.74 (s, 2h), 4.43 (td, J = 11.3, 5.4 Hz, 1H),4.09-4.01 (m, 2H), 3.89 (s, 3H), 3.85-3.74 (m, 2H), 3.53 (dd, J = 12.8,10.6 Hz, 2H), 2.96-2.75 (m, 2H), 2.19- 2.09 (m, 5H), 1.92 (d, J = 12.9Hz, 2H); m/z 461. Q Example 147

Not Determined; m/z 445. R Example 148

Not Determined; m/z 511. S Example 149

¹H NMR (400 MHz, DMSO- d₆) δ 8.69 (d, J = 1.3 Hz, 1H), 8.57 (td, J =6.9, 1.3 Hz, 1H), 8.45-8.26 (m, 2H), 7.69 (ddd, J = 8.8, 4.9, 2.5 Hz,2H), 7.48 (ddd, J = 14.9, 7.1, 1.2 Hz, 1H), 7.01 (q, J = 7.1 Hz, 1H),4.83 (d, J = 14.2 Hz, 2H), 4.40 (ddt, J = 15.4, 11.0, 5.4 Hz, 1H),4.05-3.96 (m, 2H), 3.81 (q, J = 5.9 Hz, 2H), 3.51 (dd, J = 12.8, 10.8Hz, 2H), 2.94-2.74 (m, 2H), 2.20- 2.04 (m, 4H), 1.98 (s, 1H), 1.95-1.85(m, 2H); m/z 510. S Example 150

¹H NMR (400 MHz, DMSO- d₆) δ 8.61 (dd, J = 6.6, 2.4 Hz, 1H), 8.40-8.11(m, 2H), 7.46 (dd, J = 10.3, 6.9 Hz, 1H), 7.02-6.85 (m, 3H), 4.84 (s,2H), 4.40 (tq, J = 10.4, 4.7 Hz, 1H), 4.00 (dd, J = 11.1, 4.2 Hz, 2H),3.87-3.77 (m, 5H), 3.50 (t, J = 11.7 Hz, 2H), 2.94-2.75 (m, 2H), 2.19-2.03 (m, 4H), 1.97 (s, 1H), 1.89 (dd, J = 11.8, 3.3 Hz, 2H); m/z 490. SExample 151

¹H NMR (400 MHz, DMSO- d₆) δ 8.58-8.52 (m, 1H), 8.51 (s, 1H), 7.66-7.50(m, 2H), 7.51-7.40 (m, 1H), 7.36 (q, J = 8.1 Hz, 1H), 6.97 (q, J = 6.7Hz, 1H), 6.93-6.85 (m, 1H), 4.89-4.76 (m, 2H), 4.40 (dq, J = 11.3, 6.1Hz, 1H), 4.03-3.96 (m, 2H), 3.87- 3.76 (m, 5H), 3.50 (t, J = 11.9 Hz,2H), 2.98-2.78 (m, 2H), 2.18-2.04 (m, 4H), 1.98 (s, 1H), 1.89 (d, J =13.0 Hz, 2H); m/z 472. S Example 152

¹H NMR (400 MHz, DMSO- d₆) δ 8.53 (ddd, J = 6.7, 4.4, 1.3 Hz, 1H), 8.44(d, J = 1.9 Hz, 1H), 7.92-7.82 (m, 1H), 7.82-7.75 (m, 1H), 7.45 (ddd, J= 13.0, 7.1, 1.2 Hz, 1H), 7.24 (dt, J = 14.5, 9.0 Hz, 1H), 6.97 (q, J =6.8 Hz, 1H), 4.84 (d, J = 5.1 Hz, 2H), 4.39 (dt, J = 11.2, 6.0 Hz, 1H),4.00 (d, J = 11.4 Hz, 2H), 3.88 (s, 3H), 3.82 (dt, J = 11.6, 5.8 Hz,2H), 3.55-3.43 (m, 2H), 2.97-2.75 (m, 2H), 2.17-2.05 (m, 4H), 1.99 (s,1H), 1.89 (d, J = 12.6 Hz, 2H); m/z 490. S Example 153

¹H NMR (400 MHz, DMSO- d₆) δ 11.42-11.29 (m, 1H), 8.54 (td, J = 6.6,6.2, 1.3 Hz, 1H), 8.42 (s, 1H), 8.20-7.81 (m, 2H), 7.49-7.37 (m, 2H),7.21-7.08 (m, 2H), 6.93 (q, J = 7.1 Hz, 1H), 4.98-4.85 (m, 2H), 4.40(tt, J = 10.4, 4.7 Hz, 1H), 4.05-3.96 (m, 2H), 3.82 (dt, J = 12.1, 5.7Hz, 2H), 3.51 (td, J = 11.9, 2.0 Hz, 2H), 3.01-2.79 (m, 2H), 2.21- 2.05(m, 4H), 1.98-1.86 (m, 3H); m/z 481. S Example 154

¹H NMR (400 MHz, DMSO- d₆) δ 9.44 (s, 1H), 8.54 (ddd, J = 6.7, 2.8, 1.2Hz, 1H), 8.40 (d, J = 3.1 Hz, 1H), 7.49- 7.35 (m, 3H), 7.22 (td, J =7.8, 3.0 Hz, 1H), 7.01-6.91 (m, 1H), 6.76-6.68 (m, 1H), 4.86 (s, 1H),4.76 (s, 1H), 4.44-4.34 (m, 1H), 4.00 (d, J = 11.3 Hz, 2H), 3.83 (q, J =5.6 Hz, 2H), 3.50 (dd, J = 12.6, 10.8 Hz, 2H), 2.94 (d, J = 5.8 Hz, 1H),2.83 (d, J = 5.9 Hz, 1H), 2.20-2.04 (m, 4H), 1.99 (s, 1H), 1.89 (d, J =12.7 Hz, 2H); m/z 458. S Example 155

¹H NMR (400 MHz, DMSO- d₆) δ 8.53 (ddd, J = 6.7, 4.0, 1.3 Hz, 1H), 8.37(d, J = 1.8 Hz, 1H), 8.03-7.96 (m, 1H), 7.95-7.88 (m, 1H), 7.43 (ddd, J= 13.4, 7.1, 1.3 Hz, 1H), 7.08-6.98 (m, 2H), 6.95 (q, J = 6.8 Hz, 1H),4.85 (d, J = 13.8 Hz, 2H), 4.39 (tt, J = 10.5, 5.1 Hz, 1H), 4.00 (d, J =11.7 Hz, 2H), 3.87-3.77 (m, 5H), 3.50 (t, J = 11.7 Hz, 2H), 2.98-2.77(m, 2H), 2.19- 2.04 (m, 4H), 1.99 (s, 1H), 1.94-1.85 (m, 2H); m/z 472. SExample 156

¹H NMR (400 MHz, DMSO- d₆) δ 8.61-8.55 (m, 1H), 8.54 (s, 1H), 8.24-8.15(m, 1H), 8.15-8.07 (m, 1H), 7.52-7.38 (m, 3H), 6.99 (q, J = 6.6 Hz, 1H),4.84 (s, 2H), 4.40 (tt, J = 10.7, 4.8 Hz, 1H), 4.00 (dd, J = 11.3, 4.4Hz, 2H), 3.82 (dt, J = 11.8, 5.8 Hz, 2H), 3.50 (td, J = 12.1, 2.1 Hz,2H), 2.98- 2.74 (m, 2H), 2.19-2.03 (m, 4H), 1.97 (s, 1H), 1.89 (d, J =13.6 Hz, 2H); m/z 526. S Example 157

¹H NMR (400 MHz, DMSO- d₆) δ 9.01 (d, J = 4.7 Hz, 1H), 7.93-7.85 (m,2H), 7.62 (d, J = 8.9 Hz, 1H), 7.38 (dt, J = 9.0, 6.9 Hz, 1H), 7.09-6.93(m, 3H), 4.67 (s, 2H), 4.53 (tt, J = 11.2, 4.0 Hz, 1H), 4.06 (dd, J =10.8, 4.7 Hz, 2H), 3.88-3.77 (m, 5H), 3.55 (tt, J = 11.6, 2.1 Hz, 2H),2.97- 2.78 (m, 2H), 2.24-2.04 (m, 5H), 2.05-1.94 (m, 2H); m/z 472. SExample 158

¹H NMR (400 MHz, DMSO- d₆) δ 9.51-9.37 (m, 1H), 8.82 (dt, J = 4.9, 1.6Hz, 1H), 8.72-8.54 (m, 1H), 7.84 (dd, J = 7.9, 1.1 Hz, 1H), 7.73- 7.63(m, 2H), 7.52 (t, J = 7.8 Hz, 1H), 4.86-4.72 (m, 2H), 4.44 (ddt, J =11.3, 8.3, 4.2 Hz, 1H), 4.07-3.98 (m, 2H), 3.92-3.79 (m, 2H), 3.52 (td,J = 11.9, 2.1 Hz, 2H), 3.03- 2.79 (m, 2H), 2.22-2.04 (m, 4H), 2.01 (s,1H), 1.97-1.88 (m, 2H); m/z 444. T Example 159

¹H NMR (400 MHz, DMSO- d₆) δ 8.32-8.11 (m, 2H), 7.74 (dd, J = 8.0, 1.1Hz, 1H), 7.62 (dd, J = 7.6, 1.2 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.23-7.12 (m, 2H), 4.80-4.70 (m, 2H), 4.49-4.37 (m, 1H), 4.07-3.98 (m, 2H),3.91- 3.79 (m ,5H), 3.52 (td, J = 1.9, 2.1 Hz, 2H), 2.95-2.75 (m, 2H),2.22-2.06 (m, 4H), 2.01 (s, 1H), 1.92 (dd, J = 13.1, 3.8 Hz, 2H); m/z473. T Example 160

¹H NMR (400 MHz, DMSO- d₆, 24/26 H) δ 10.50 (d, J = 3.6 Hz, 1H),8.29-8.10 (m, 1H), 8.04 (d, J = 0.8 Hz, 1H), 7.95-7.84 (m, 1H), 7.84-7.71 (m, 1H), 7.68-7.51 (m, 2H), 5.00 (dd, J = 6.7, 4.7 Hz, 1H), 4.70(s, 2H), 4.16-3.99 (m, 2H), 3.98-3.67 (m, 6H), 3.00-2.84 (m, 1H), 2.44-2.26 (m, 2H), 2.18-1.97 (m, 3H); m/z 435.2. U Example 161

¹H NMR (400 MHz, DMSO- d₆) δ 10.76 (s, 1H), 8.25- 8.09 (m, 1H), 8.01(dd, J = 8.8, 1.7 Hz, 2H), 7.96-7.76 (m, 4H), 7.63 (td, J = 7.7, 3.3 Hz,1H), 5.15-4.86 (m, 1H), 4.70 (s, 2H), 4.24-3.99 (m, 2H), 3.99-3.82 (m,4H), 3.77 (dt, J = 11.3, 4.2 Hz, 4H), 2.11 (d, J = 9.7 Hz, 3H); m/z456.2. U Example 162

¹H NMR (400 MHz, DMSO- d₆) δ 10.68 (d, J = 4.4 Hz, 1H), 8.82 (dd, J =4.2, 1.7 Hz, 1H), 8.66-8.49 (m, 1H), 8.40- 8.29 (m, 1H), 8.29-8.14 (m,1H), 8.12-7.91 (m, 3H), 7.84 (dd, J = 7.9, 1.5 Hz, 1H), 7.64 (td, J =7.7, 2.7 Hz, 1H), 7.51 (dd, J = 8.3, 4.2 Hz, 1H), 5.01 (qd, J = 6.7, 4.6Hz, 1H), 4.73 (d, J = 3.0 Hz, 2H), 4.19- 4.00 (m, 2H), 4.00-3.84 (m,3H), 3.78 (d, J = 5.9 Hz, 3H), 2.36 (qd, J = 7.1, 2.9 Hz, 2H), 2.21-1.98(m, 3H); m/z 482.2. U Example 163

¹H NMR (400 MHz, DMSO- d₆, 26/28 H) δ 10.53 (d, J = 3.6 Hz, 1H), 8.29(dt, J = 1.9, 1.0 Hz, 1H), 8.19 (dt, J = 11.5, 1.8 Hz, 1H), 8.05-7.91(m, 2H), 7.91-7.78 (m, 1H), 7.71 (dd, J = 8.6, 0.9 Hz, 1H), 7.63 (t, J =7.7 Hz, 1H), 7.40 (ddd, J = 8.7, 2.9, 1.7 Hz, 1H), 5.08-4.90 (m, 1H),4.72 (t, J = 2.3 Hz, 2H), 4.23- 3.97 (m, 5H), 3.98-3.82 (m, 2H), 3.78(d, J = 5.9 Hz, 1H), 2.42-2.29 (m, 3H), 2.12 (d, J = 7.5 Hz, 3H); m/z485.2. U Example 164

¹H NMR (400 MHz, DMSO- d₆) δ 10.51 (d, J = 3.6 Hz, 1H), 8.31-8.10 (m,2H), 8.06- 7.89 (m, 3H), 7.86-7.77 (m, 1H), 7.72 (t, J = 1.3 Hz, 2H),7.71-7.56 (m, 3H), 5.09- 4.91 (m, 1H), 4.71 (s, 2H), 4.08 (tt, J = 9.0,7.0 Hz, 2H), 3.97-3.82 (m, 2H), 3.77 (q, J = 6.4, 5.5 Hz, 2H), 2.43-2.25 (m, 4H), 2.11 (d, J = 7.9 Hz, 3H); m/z 497.2. U Example 165

¹H NMR (400 MHz, DMSO- d₆) δ 10.39 (d, J = 3.6 Hz, 1H), 8.64 (s, 1H),8.14 (dt, J = 9.2, 1.8 Hz, 1H), 7.98 (s, 1H), 7.95-7.84 (m, 2H), 7.77(dd, J = 8.6, 1.9 Hz, 2H), 7.60 (td, J = 7.8, 2.5 Hz, 1H), 7.36- 7.25(m, 2H), 5.38 (s, 2H), 4.99 (qd, J = 6.6, 4.6 Hz, 1H), 4.70 (d, J = 3.7Hz, 2H), 4.16- 3.97 (m, 2H), 3.97-3.82 (m, 4H), 3.77 (q, J = 7.0, 6.0Hz, 2H), 2.34 (qd, J = 6.8, 2.7 Hz, 2H), 2.16-2.02 (m, 3H); m/z 512.2. UExample 166

Not Determined; m/z 511.2. U Example 167

¹H NMR (400 MHz, DMSO- d₆) δ 12.77 (s, 1H), 8.57 (s, 1H), 8.36-8.07 (m,1H), 8.00- 7.68 (m, 1H), 7.68-7.39 (m, 3H), 7.25 (dqd, J = 8.8, 7.4, 1.3Hz, 2H), 5.18-4.89 (m, 1H), 4.76 (d, J = 14.1 Hz, 2H), 4.27-3.98 (m,2H), 3.99- 3.84 (m, 2H), 2.97-2.83 (m, 1H), 2.77 (s, 3H), 2.42- 2.28 (m,5H), 2.13 (d, J = 11.2 Hz, 3H); m/z 485.2. U Example 168

¹H NMR (400 MHz, DMSO- d₆, 26/27 H) δ 10.82 (s, 1H), 9.16 (dd, J = 2.5,0.8 Hz, 1H), 8.87 (dt, J = 2.5, 1.3 Hz, 1H), 8.42-8.10 (m, 1H), 8.16-7.97 (m, 3H), 7.93-7.79 (m, 1H), 7.76-7.53 (m, 2H), 5.01 (qd, J = 6.7,4.6 Hz, 1H), 4.73 (d, J = 3.7 Hz, 2H), 4.20- 3.98 (m, 2H), 3.98-3.84 (m,2H), 2.89 (t, J = 5.9 Hz, 1H), 2.78 (d, J = 6.2 Hz, 1H), 2.44- 2.27 (m,4H), 2.12 (d, J = 6.3 Hz, 3H); m/z 482.2. U Example 169

Not Determined; m/z 446.2. U Example 170

¹H NMR (400 MHz, DMSO- d₆) δ 10.76 (s, 1H), 9.18 (d, J = 1.4 Hz, 2H),8.93 (s, 1H), 8.21 (dt, J = 12.9, 1.7 Hz, 1H), 8.07-7.78 (m, 2H), 7.64(td, J = 7.8, 3.4 Hz, 1H), 5.00 (qd, J = 6.7, 4.7 Hz, 1H), 4.21- 3.98(m, 2H), 3.98-3.66 (m, 6H), 2.35 (qd, J = 6.8, 2.3 Hz, 4H), 2.11 (d, J =8.9 Hz, 3H); m/z 433.2. U Example 171

¹H NMR (400 MHz, DMSO- d₆) δ 10.56 (s, 1H), 8.94 (dd, J = 2.5, 0.9 Hz,1H), 8.32 (dd, J = 4.6, 1.5 Hz, 1H), 8.27- 8.12 (m, 2H), 8.02-7.88 (m,1H), 7.88-7.77 (m, 1H), 7.62 (td, J = 7.7, 2.9 Hz, 1H), 7.41 (ddt, J =8.4, 4.8, 0.8 Hz, 1H), 5.00 (qd, J = 6.6, 4.6 Hz, 1H), 4.71 (d, J = 3.6Hz, 2H), 4.19- 3.99 (m, 2H), 3.99-3.81 (m, 3H), 3.77 (q, J = 6.9, 5.7Hz, 2H), 2.98-2.85 (m, 1H), 2.35 (qd, J = 6.7, 2.4 Hz, 2H), 2.18-1.98(m, 3H); m/z 432.2. U Example 172

¹H NMR (400 MHz, DMSO- d₆) δ 10.38 (d, J = 4.7 Hz, 1H), 8.30-8.22 (m,1H), 8.18 (dt, J = 10.6, 1.7 Hz, 1H), 8.03 (dd, J = 1.9, 0.9 Hz, 1H),7.92 (dq, J = 7.8, 1.6 Hz, 1H), 7.87-7.76 (m, 1H), 7.69 (d, J = 1.9 Hz,1H), 7.66-7.54 (m, 2H), 5.00 (qd, J = 6.6, 4.7 Hz, 1H), 4.72 (d, J = 3.8Hz, 2H), 4.17-3.97 (m, 5H), 3.99- 3.82 (m, 2H), 3.77 (q, J = 7.0, 5.7Hz, 2H), 2.89 (t, J = 5.8 Hz, 1H), 2.77 (s, 1H), 2.43- 2.25 (m, 2H),2.11 (d, J = 7.6 Hz, 3H); m/z 485.2. U Example 173

¹H NMR (400 MHz, CDCl₃) δ 7.34-7.20 (m, 3H), 4.99- 4.87 (m, 1H),4.55-4.27 (m, 4H), 4.24-4.04 (m, 3H), 4.00- 3.75 (m, 2H), 3.74-3.65 (m,2H), 3.54 (t, J = 12.0 Hz, 2H), 2.89-2.72 (m, 2H), 2.42- 2.26 (m, 2H),2.20-2.11 (m, 3H), 1.95-1.83 (m, 2H), 1.19- (t, J = 6.8 Hz, 6H); m/z437. V Example 174

¹H NMR (400 MHz, CDCl₃) δ 7.34-7.18 (m, 3H), 4.54 (s, 2H), 4.53-4.45 (m,1H), 4.43- 4.34 (m, 2H), 4.25-4.07 (m, 3H), 3.99-3.76 (m, 2H), 3.75-3.66 (m, 2H), 3.54 (t, J = 12.0 Hz, 2H), 2.90-2.73 (m, 2H), 2.42-2.27(m, 2H), 2.20- 2.11 (m, 3H), 1.94-1.77 (m, 4H), 1.74-1.58 (m, 4H), 1.56-1.36 (m, 4H); m/z 477. V Example 175

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.15 (m, 3H), 5.09- 4.95 (m, 1H),4.49-4.32 (m, 1H), 4.16-4.02 (m, 3H), 3.91- 3.69 (m, 2H), 3.65-3.61 (m,2H), 3.49 (t, J = 12.0 Hz, 2H), 2.80-2.68 (m, 2H), 2.35- 2.20 (m, 2H),2.18-2.03 (m, 7H), 1.88-1.79 (m, 2H), 1.75- 1.59 (m, 2H); m/z 449. V

Example 176

IC₅₀ Measurements for Inhibitors Using CBP TR-FRET Binding Assay

His/Flag epitope tagged CBP was cloned, expressed, and purified tohomogeneity. CBP binding and inhibition was assessed by monitoring theengagement of a biotinylated small molecule compound with the targetusing the TR-FRET assay technology (Perkin-Elmer). Specifically, in a384 well ProxiPlate CBP (4 nM final) was combined with biotin-ligand (60nM final) in 50 mM HEPES (pH 7.5), 50 mM NaCl, 1 mM TCEP, 0.01% (w/v)BSA, and 0.008% (w/v) Brij-35 either in the presence of DMSO (final 0.2%DMSO) or compound dilution series in DMSO. After 10 minutes incubationat room temperature, a mixture Eu-W1024 Anti-6xHis antibody (“6xHis” isdisclosed as SEQ ID NO: 3) (Perkin Elmer ADO 110) and SureLight™Allophycocyanin-Streptavidin (APC-SA, Perkin Elmer CR130-100) were addedto a final concentrations of 0.2 nMolar antibody and 50 nMolar APC-SA,respectively. After twenty minutes of equilibration, the plates wereread on an Envision instrument and IC50s calculated using a fourparameter non-linear curve fit.

MYC_RPL19 QuantiGene Assay in MV-4-11 Cells

QuantiGene 2.0 Reagent system, Affymetrix: HUMAN MYCN; V-mycmyelocytomatosis viral related oncogene, neuroblastoma derived (avian);NM_005378 SA-15008. 10,000 MV-4-11 cells (GNE in-house) were plated in75 ul complete media: RPMI-1640 (GNE in-house), 10% FBS (LifeTechnologies, cat. no. 10082), 1% Pen-strep (GNE in-house), in 96 wellclear flat bottom plates (Costar, cat. no. 3595). 25 ul compound wasadded for 4 hours at 37 deg C. in a 1:3 serial dilution 10-point doseresponse, with a final DMSO concentration=0.2%. The cells were thenlysed according to the assay kit's protocol and frozen at −80 deg C. Thefollowing day, an appropriate volume of Working Probe Set was preparedby combining the following reagents in the order listed: Nuclease-freewater, Lysis Mixture, Blocking Reagent, and 2.0 Probe Set (MYC orRPL19). 20 ul of the working probe set was added into each assay well onthe capture plate, and then 80 ul of the lysates were transferred intothe assay plates. The capture plate was placed in a 55 deg C. incubatorfor overnight hybridization (16-20 hours). The following day, washbuffer was prepared according to manufacturer's recommendations. Thecapture plates were washed with 300 ul per well of 1× wash buffer threetimes. Then 100 ul Pre-Amplifier was added to the plate for a 60 minuteincubation at 55 deg C. After the incubation, the capture plate waswashed with 300 ul per well of 1× wash buffer three times, and 100 ulAmplifier was added to the plate for a 60 minute incubation at 55 deg C.The capture plate was again washed with 300 ul per well of 1× washbuffer three times, and 100 ul Label Probe was added to the plate for a60 minute incubation at 50 deg C. Then the capture plate was washed with300 ul per well of 1× wash buffer three times, and 100 ul 2.0 Substratewas added to each well of the plate. The plates were incubated at RT for5 minutes in the dark and read on the Envision using the luminescenceprotocol, with an integration time set at 0.2 seconds.

Data for representative compounds from the assays described above isprovided in the following table.

CBP HTRF Myc Example Compound IC₅₀ (μM) IC₅₀ (μM) 1

0.0935 2

0.0972 3

0.0174 4

0.0581 5

0.0687 6

0.0493 7

0.0240 8

0.0687 9

0.00113 0.0321 10

0.00115 0.0153 11

0.00238 0.114 12

0.123 13

0.0598 14

0.00342 0.203 15

0.00232 0.0540 16

0.0899 17

0.0553 18

0.0676 19

0.00674 1.09 20

0.0813 21

0.0263 6.16 22

0.0248 23

0.0167 24

0.00205 0.0263 25

0.00107 0.00596 26

0.00643 27

0.0167 28

0.0416 29

0.0595 30

0.00502 0.198 31

0.00171 0.0646 32

0.00564 0.0728 33

0.00237 0.0988 34

0.00145 0.0592 35

0.0182 36

0.00139 0.0465 37

0.00242 0.164 38

0.0165 1.43 39

0.00577 0.617 40

0.0176 0.727 41

0.0265 42

0.0104 43

0.0547 44

0.00629 45

0.00154 0.481 46

0.00097 0.00903 47

0.00191 0.0619 48

0.00961 0.568 49

0.00142 0.0559 50

0.124 51

0.121 52

53

0.00238 0.0520 54

0.124 55

0.0999 56

0.0308 57

0.0431 58

0.109 59

0.0525 60

0.0080 61

0.103 62

0.0430 63

0.0999 64

0.0378 65

0.0849 66

0.0205 67

0.0300 68

0.0159 69

0.0155 70

0.00514 71

0.00657 72

0.125 73

0.141 74

0.0902 75

0.0134 0.523 76

0.0272 77

0.0233 78

0.0294 79

0.0308 80

0.0378 81

0.0648 82

0.0805 83

0.00270 0.0662 84

0.0222 8.87 85

0.00212 0.052 86

0.00233 0.0305 87

0.000997 0.0180 88

0.00116 0.0319 89

0.00192 90

0.00110 0.0168 91

0.00117 0.0283 92

0.000760 0.00735 93

0.000910 94

0.00100 0.00722 95

0.0357 96

0.00294 0.0755 97

0.00334 0.221 98

0.00278 0.109 99

0.0814 100

0.0788 101

0.00641 0.330 102

0.0568 103

0.0410 104

0.0345 105

0.0338 106

0.0111 107

0.0954 108

0.0576 109

0.0912 110

0.0677 111

0.00362 0.152 112

0.00349 0.249 113

0.00299 0.863 114

0.00349 1.15 115

0.00898 0.942 116

0.0245 117

0.0128 1.51 118

0.00281 0.850 119

0.00282 1.18 120

0.00369 0.119 121

0.00582 1.12 122

0.00408 0.563 123

0.0132 2.49 124

0.00215 0.491 125

0.00417 0.925 126

0.00771 0.374 127

0.0145 128

0.00244 0.280 129

0.00185 0.605 130

0.00725 0.285 131

0.094 132

0.133 133

0.0168 0.623 134

0.123 135

0.0354 1.01 136

0.133 137

0.054 138

0.132 139

0.131 140

0.0445 2.71 141

0.115 142

0.0423 0.504 143

0.0581 144

0.0295 0.761 145

0.013 4.42 146

0.0298 147

0.00609 0.263 148

0.0797 149

0.123 150

0.0667 151

0.128 152

0.0461 >10 153

0.0957 154

0.101 155

0.0691 156

0.107 157

0.00446 1.04 158

0.0193 5.32 159

0.00411 1.58 160

0.0737 161

0.082 162

0.0329 163

0.0497 164

0.0831 165

0.0442 166

0.0365 167

0.011 168

0.0326 169

0.0592 170

0.123 171

0.104 172

0.0392 173

0.0305 174

0.0119 175

0.0104 0.122

Exemplification of CBP/EP300 Inhibitors for the Treatment of FibroticDisease

Cell Culture:

Collagen 1-coated 384-well plates (BD Biosciences cat #356667) wereseeded with Normal Human Lung Fibroblasts (Lonza cat #CC-2512) at 2000cells per well in 50 μl DMEM (Genentech) containing 0.5% fetal bovineserum (Sigma cat #F2442). After 16 hours, the indicated compounds wereadded to cells at final concentrations ranging from 10 μM to 0.005 nM inan 8-fold dilution series. After one hour, TGF beta (Genentech) wasadded to cells to a final concentration of 10 ng/ml. All treatments wereperformed in duplicate.

Animal Study:

Bleomycin was administered to mice via subcutaneous implantation of anosmotic pump (Alzet cat #1007D). After bleomycin administration, micewere treated with compounds by oral gavage. Mice received either MCTvehicle (0.5% w/v methylcellulose, 0.2% w/v polysorbate 80), G0272 inMCT at 5 mg/kg twice daily, G0272 in MCT at 15 mg/kg twice daily, G5049in MCT at 5 mg/kg twice daily, G5049 in MCT at 15 mg/kg twice daily,G3486 in MCT at 15 mg/kg twice daily, or G3486 in MCT at 45 mg/kg twicedaily. To label newly synthesized collagen, mice were injectedintraperitoneally with 35 ml/kg heavy water (Sigma Aldrich, cat #151882)in two doses and heavy water was provided in drinking water. At studytermination, blood samples were collected by retro-orbital bleed underisoflurane anesthesia and mice were euthanized. Upper right lung lobeswere placed in glass vials and snap frozen in liquid nitrogen for massspectrometry. The lower right lung lobe was placed in RNAlater forexpression analysis, and frozen at −20° C.

Lung Hydroxyproline Determination:

Lungs were thawed, dried overnight at 80° C., then hydrolyzed at 110° C.overnight in 6N HCl. The remainder of this paragraph was performed byKineMed, Emeryville Calif.). A 100 μl aliquot of tissue hydrolysatereceived a spike containing 1 μg ²H3-labeled hydroxyproline (D3-OHP;trans-4-Hydroxy-L-proline-2,5,5-d3; CDN), and then dried under vacuumand re-suspended in a solution of 50% acetonitrile, 50 mM K₂HPO₄ andpentafluorobenzyl bromide before incubation. Derivatives were extractedinto ethyl acetate, and the top layer was removed and dried by vacuumcentrifugation. In order to acetylate the hydroxyl moiety ofhydroxyproline, samples were incubated with a solution of acetonitrile,N-Methyl-N-[tert-butyldimethyl-silyl]trifluoroacetamide andmethylimidizole. This material was extracted in petroleum ether anddried with Na₂SO₄. The derivatized hydroxyproline was analyzed by GC/MS,performed in the negative chemical ionization mode. Selected ionmonitoring was performed on ions with mass-to-charge ratios (m/z) 445,446, 447, and 448 which include all of the carbon-hydrogen bonds fromhydroxyproline. Incorporation of ²H into hydroxyproline was calculatedas the molar fraction of molecules with one excess mass unit above thenatural abundance fraction (EM1). Fractional collagen synthesis (f) wascalculated as the ratio of the EM1 value in protein-bound hydroxyprolineto the maximal value possible at the body water enrichment present. Thismethod has previously been described (Gardner, J. L., et al.,Measurement of liver collagen synthesis by heavy water labeling: effectsof profibrotic toxicants and antifibrotic interventions. Am J PhysiolGastrointest Liver Physiol, 2007. 292(6): p. G1695-705). Additionally,hydroxyproline content in each tissue sample was determined by comparingthe abundance in the m3 448 m/z channel representing the D3-OHP internalstandard in each sample with that the m0 445 m/z ion. A set of standardswith known OHP/D3-OHP concentration ratios was analyzed alongside thesamples. ²H₂O enrichment in plasma was determined using a previouslydescribed method (Previs S F, Hazey J W, Diraison F, Beylot M, David F,Brunengraber H (1996) Assay of the deuterium enrichment of water viaacetylene. J Mass Spectrom 31:639-642). Briefly body water is evaporatedfrom plasma by overnight incubation at 80° C. Samples are then mixed in10M NaOH and acetone followed by a second overnight incubation. Thismaterial was extracted in hexane and dried with Na₂SO₄ prior to GCMSanalysis.

RNA Isolation:

For cultured cells, after 24 hours of treatment with TGF beta andCBP/p300 inhibitor, mRNA was isolated with the Turbocapture 384 mRNA kit(Qiagen cat #72271) according to the manufacturers' instructions andeluted with 30 μl elution buffer. For lungs, tissues were thawed,removed from RNAlater, homogenized in GentleMACS M tubes (MiltenyiBiotec cat #130-093-236) and RNA extracted with the RNeasy 96 kit(Qiagen cat #74182) according to the manufacturers instructions.

Expression Analysis:

First-strand cDNA was synthesized using 14 μl mRNA for cultured cellsand 150 ng RNA for lung. The High Capacity cDNA Reverse TranscriptionKit (Life Technologies cat #4368814) was used according to themanufacturers protocol. Specific target amplification was performedusing 1.25 μl cDNA, Taqman assays (Life Technologies cat #4331182) at afinal concentration of 0.2×, and Taqman Preamp Master Mix (LifeTechnologies cat #4488593) and subsequently diluted according to theprotocol for Fluidigm qPCR (Fluidigm Corp). Samples and assays weremixed with loading buffers and loaded onto 192.24 IFCs (Fluidigm cat#100-6266) according to the manufacturers instructions. Reactions weremixed using the IFC controller RX (Fluidigm) then amplified and measuredusing the Biomark system (Fluidigm). For cultured cells, relativeexpression of each target gene was determined using the ΔCt method,normalizing to the Ct for HPRT1 using Excel software (Microsoft). Togenerate heat maps, TGF beta-mediated expression increase for each genein the presence of CBP/p300 inhibitor was divided by the increase in theabsence of CBP/p300 inhibitor using Excel (i.e.(2^(−ΔCt, SMI+TGFb)−2^(−ΔCt, SMI, no TGFb))/(2^(−ΔCt, TGFb)−2^(−ΔCt, no TGFb))).Line graphs of 2^(−ΔCt) values were generated using Prism software(Graphpad). For lung, relative expression of each target gene wasdetermined using the ΔΔCt method, normalizing to the Ct for GAPDH andthe vehicle control group. Heat maps were generated with Excel software(Microsoft).

While a number of embodiments have been described, these examples may bealtered to provide other embodiments that utilize the compounds andmethods described herein. Therefore, the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim:
 1. A compound of formula (Ia):

or a salt thereof, wherein: R¹ is

R² is —C(O)—N(R^(e))₂, or —C(O)—R^(e); Y is selected from the groupconsisting of:

each R^(e) is independently selected from hydrogen, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, and C₂₋₅cycloalkyl, wherein each C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, and C₂₋₅cycloalkyl is optionally substitutedwith one or more groups independently selected from oxo, halo, amino,hydroxyl, C₁₋₃alkoxy, and C₁-C₃ alkyl that is optionally substitutedwith one or more groups independently selected from halo.
 2. Thecompound or salt of claim 1 wherein R¹ is


3. The compound or salt of claim 1 wherein Y is selected from the groupconsisting of:


4. The compound or salt of claim 1 wherein Y is selected from the groupconsisting of:


5. A compound or salt thereof selected from the group consisting of:

or a salt thereof.
 6. A composition comprising a compound as describedin claim 1 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable adjuvant, carrier, or vehicle.
 7. A methodfor treating a CBP and/or EP300-mediated cancer in an animal byselectively inhibiting a bromodomain of the CBP and/or EP300 in theanimal, comprising administering an effective amount of a compound or apharmaceutically acceptable salt thereof, as described in claim 1, tothe animal, wherein the animal has a mutation in the CBP and/or EP300,and wherein the cancer is selected from lung cancer, breast cancer,pancreatic cancer, colorectal cancer, or melanoma.
 8. A compositioncomprising a compound as described in claim 5 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable adjuvant,carrier, or vehicle.